54th Annual Meeting

Birth Defects Research (Part A) 103:311–347 (2015)

Birth Defects Research (Part A) Clinical and Molecular Teratology 103:311–347 (2015)

312

Birth Defects Research (Part A) 103:311–347 (2015)

TERATOLOGY SOCIETY PROGRAM

TERATOLOGY SOCIETY PROGRAM

313

Birth Defects Research (Part A) 103:311–347 (2015)

314

TERATOLOGY SOCIETY PROGRAM

Program Overview FRIDAY, JUNE 26, 2015

3:00 PM–6:00 PM Registration Open 3:00 PM–6:00 PM Speaker Ready Room Open 6:00 PM–9:00 PM Council 1A Meeting SATURDAY, JUNE 27, 2015

7:00 AM–6:00 PM Registration Open 7:00 AM–6:00 PM Speaker Ready Room Open 7:30 AM–8:00 AM Education Course Coffee and Continental Breakfast 8:00 AM–12:00 Noon Education Course Session 1 Occupational and Environmental Exposures: Reproductive and Developmental Hazards in the Workplace and Home 12:00 Noon–1:30 PM Student Affairs Committee Meeting 1:30 PM–5:00 PM Education Course Session 2 Ethics and Ethical Implications 5:30 PM–7:30 PM Student and Postdoctoral Fellow Mixer 6:30 PM–9:30 PM Council 1B Meeting, Committee Reports, and Leadership Training SUNDAY, JUNE 28, 2015

7:00 AM–6:00 PM Registration Open 7:00 AM–6:00 PM Speaker Ready Room Open 7:00 AM–8:00 AM Dine with a Teratology Ambassador 7:00 AM–8:00 AM BDRB Editorial Board Meeting 8:00 AM–8:15 AM President’s Welcome 8:15 AM–9:00 AM Josef Warkany Lecture (Joint with OTIS) Developmental Toxicology: Putting the Puzzle Together 9:00 AM–12:00 Noon Student/Postdoctoral Fellow Platform Session 1 10:00 AM–10:30 AM Spouse and Guest Meet-and-Greet 12:00 Noon–1:30 PM Constitution and Bylaws Committee Meeting

12:00 Noon–1:30 PM Science Committee Meeting 12:00 Noon–1:30 PM Student and Postdoctoral Lunch Workshop: Transitioning from Graduate School, to Postdoctoral Fellow, to First Job 1:30 PM–2:00 PM F. Clarke Fraser New Investigator Award: The Risk of a Broken Heart 2:00 PM–2:30 PM James G. Wilson Publication Award: The Microbiome in Early Life: Self-Completion and Microbiota Protection As Health Priorities 2:30 PM–5:30 PM Paternal Exposures Impact Progeny Outcome by Altering the Sperm Genome and Epigenome Symposium 2:30 PM–5:30 PM Platform Session 2: Abnormal Neural Development 5:30 PM–6:00 PM Patricia Rodier Mid-Career Award in Research and Mentoring (Joint with NBTS) Development Causes and Consequences of Drug Abuse 6:00 PM–7:30 PM Welcome Reception, Silent Auction, and Exhibits Attended (Joint with INA and NBTS) 7:30 PM–8:30 PM Communications Working Group Meeting 7:30 PM–8:30 PM Publications Committee Meeting MONDAY, JUNE 29, 2015

7:00 AM–6:00 PM Registration Open 7:00 AM–6:00 PM Speaker Ready Room Open 7:00 AM–8:00 AM 2016 Program Committee Meeting 8:00 AM–9:00 AM Remembering F. Clarke Fraser 9:00 AM–12:00 Noon Wiley-Blackwell Symposium: Are Human Skeletal Malformations the Result of Embryonic Arterial Dysgenesis? 9:00 AM–12:00 Noon Regulatory Neurodevelopmental Testing: New Guiding Principles for Harmonization of Data Collection and Analysis Workshop (Joint with NBTS) 12:00 Noon–1:30 PM BDRA Editorial Board

Birth Defects Research (Part A) 103:311–347 (2015)

12:00 Noon–1:30 PM Past Presidents’ and Honorees’ Luncheon (By Invitation Only) 1:30 PM–5:30 PM March of Dimes Symposium (Joint with OTIS): Perinatal Outcomes following Assisted Reproductive Technologies 1:30 PM–5:30 PM Reactive Oxygen Species, Oxidative Stress, and Redox Signaling in Developmental Toxicology Symposium 5:30 PM–7:30 PM Poster Session 1 and Exhibits Attended (Joint with INA, NBTS, and OTIS) 7:30 PM–10:00 PM Teratology Society and MARTA Student Career Event TUESDAY, JUNE 30, 2015

7:00 AM–6:00 PM Registration Open 7:00 AM–6:00 PM Speaker Ready Room Open 6:30 AM–7:00 AM Sunrise Mini Course: Coffee and Continental Breakfast 7:00 AM–8:30 AM Sunrise Mini Course: Life in the Genetic Fast Lane: Gene Manipulation and Genome Editing to Understand Congenital Diseases 8:30 AM–9:00 AM Robert L. Brent Lecture (Joint with OTIS) Genetic Mutations Cause Many Birth Defects: What We Learned from the FORGE Canada Project 9:00 AM–12:30 PM Public Affairs Symposium (Joint with INA, NBTS, and OTIS) Microbiomes: An Underappreciated Organ for Teratologists 9:00 AM–12:30 PM Platform Session 3: Developmental Toxicity of Pharmaceutical Products 12:30 PM–1:30 PM Membership Committee Meeting 12:30 PM–1:30 PM Public Affairs Committee Meeting 12:30 PM–1:30 PM Web Site Committee Meeting 1:30 PM–3:30 PM ILSI HESI Workshop: Contraception in Clinical Trials: From Animal Data to the Patient

3:45 PM–6:00 PM Genetic and Environment Interactions of Common Malformations Symposium 4:00 PM–6:00 PM The Pregnancy and Lactation Labeling Rule Symposium (Joint with OTIS): It’s Here, Now What? 6:00 PM–8:00 PM Poster Session 2 and Exhibits Attended 8:00 PM–9:00 PM Education Committee Meeting WEDNESDAY, JULY 1, 2015

6:30 AM–7:30 AM Teratology Society 34th Annual Volleyball Game 8:00 AM–2:30 PM Registration Open 8:00 AM–2:00 PM Speaker Ready Room Open 8:30 AM–9:30 AM Teratology Society and European Teratology Society Exchange Lecture: Endocrine Disruptors: A Regulatory Solution in Search of a Problem? Teratology Society 9:30 AM–12:30 PM Cerebral Palsy: History, Mechanisms and Prevention Symposium 9:30 AM–12:30 PM Platform Session 4: Alternative Models 10:15 AM–10:45 AM Warkany Tea 12:30 PM–1:00 PM Celebrating Ed Carney: Scientist, Friend, and Musician 1:30 PM–4:30 PM Mechanisms of Postnatal Reproductive Development/ Puberty and Methods for Evaluation Workshop 1:30 PM–4:30 PM Platform Session 5: Mechanisms of Teratogenesis 4:45 PM–6:15 PM Business Meeting 6:30 PM–7:30 PM Banquet Reception 7:30 PM–11:00 PM Banquet THURSDAY, JULY 2, 2015

7:00 AM–10:00 AM Council 2 Meeting

TERATOLOGY SOCIETY PROGRAM

315

OFFICERS (2014–2015) MARY ALICE SMITH President

EVE MYLCHREEST Secretary

LUDMILA BAKHIREVA Councilor (2013–2016)

TACEY E.K. WHITE Vice President

WAFA A. HARROUK Treasurer

STEPHEN B. HARRIS Councilor (2012–2015)

ELAINE Z. FRANCIS Past President

SARAH GLORIA OBICAN Councilor (2014–2017)

PAST PRESIDENTS OF THE SOCIETY J. WARKANY 1960–1961

J.R. MILLER 1973–1974

C.T. GRABOWSKI 1987–1988

J.M. FRIEDMAN 2001–2002

J.G. WILSON 1961–1962

E.M. JOHNSON 1974–1975

M.S. CHRISTIAN 1988–1989

W. SLIKKER JR. 2002–2003

F.C. FRASER 1962–1963

L.S. HURLEY 1975–1976

E.F. ZIMMERMAN 1989–1990

R.W. TYL 2003–2004

M.M. NELSON 1963–1964

J.L. SEVER 1976–1977

C.A. KIMMEL 1990–1991

K.L. JONES 2004–2005

D.A. KARNOFSKY 1964–1965

E.V. PERRIN 1977–1978

R.K. MILLER 1991–1992

M.S. TASSINARI 2005–2006

I.W. MONIE 1965–1966

A.R. BEAUDOIN 1978–1979

M. BARR JR. 1992–1993

E.M. FAUSTMAN 2006–2007

S.Q. COHLAN 1965–1966

R.M. HOAR 1979–1980

J.W. HANSON 1993–1994

T.B. KNUDSEN 2007–2008

M.N. RUNNER 1966–1967

C.R. SWINYARD 1980–1981

J.M. DESESSO 1994–1995

C.D. CHAMBERS 2008–2009

R.L. BRENT 1967–1968

W.J. SCOTT JR. 1981–1982

K.K. SULIK 1995–1996

B.F. HALES 2009–2010

T.H. SHEPARD 1968–1969

D.M. KOCHHAR 1982–1983

J.F. CORDERO 1996–1997

J.M. ROGERS 2010–2011

R.W. MILLER 1969–1970

R.E. STAPLES 1983–1984

P.E. MIRKES 1997–1998

J.M. GRAHAM JR. 2011–2012

J. LANGMAN 1970–1971

G.P. OAKLEY JR. 1984–1985

A.R. SCIALLI 1998–1999

E.W. CARNEY 2012–2013

A. PRUZANSKY 1971–1972

L.B. HOLMES 1985–1986

G.P. DASTON 1999–2000

E.Z. FRANCIS 2013–2014

D.G. TRASLER 1972–1973

A.G. HENDRICKX 1986–1987

R.J. KAVLOCK 2000–2001

HEADQUARTERS STAFF HEATHER CARSKADDAN Executive Director

BECCA ISAKOWER Program Manager

ELSA CANNON, CMP Meetings and Exhibits Manager

Teratology Society

1821 Michael Faraday Drive, Suite 300 • Reston, Virginia 20190 Tel:  703.438.3104 • Fax:  703.438.3113 • Email:  [email protected]

Birth Defects Research (Part A) 103:311–347 (2015)

316

TERATOLOGY SOCIETY PROGRAM

COMMITTEES OF THE TERATOLOGY SOCIETY (2014–2015)

AAALAC REPRESENTATION

CONSTITUTION AND BY-LAWS COMMITTEE

Eias Zahalka, PhD, MBA Email: [email protected]

2016 Tel: 301.796.7065

AWARDS COMMITTEE Robert G. Ellis-Hutchings, PhD Email: [email protected]

Chair Tel: 989.636.1928

Bruce K. Beyer, PhD, DABT Email: [email protected]

Vice Chair Tel: 908.981.3274

Janee Gelineau-van Waes, DVM, PhD Email: [email protected]

2017 Tel: 402.280.3457

Julia M. Gohlke, PhD Email: [email protected]

2017 Tel: 205.934.7060

Peixin Yang, PhD Email: [email protected]

2015 Tel: 410.706.8402

Joshua F. Robinson, PhD Email: [email protected]

Student/Postdoc Member 2015 Tel: 310.883.5685

John W. Kille, PhD, DABT Email: [email protected]

Chair Tel: 908.236.6182

Connie J. Kappeler, PhD Email: [email protected]

2016 Tel: 419.289.8700

L. David Wise, PhD Email: [email protected]

2017 Tel: 610.804.5117

Mark E. Hurtt, PhD Email: [email protected]

Past Chair Tel: 860.715.3118

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

COUNCIL Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

Tacey E.K. White, PhD Email: [email protected]

Vice President Tel: 267.216.7470

Ludmila Bakhireva, MD, PhD, MPH Email: [email protected]

Council Liaison Tel: 505.272.2545

Elaine Z. Francis, PhD Email: [email protected]

Past President Tel: 609.822.0217

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

Eve Mylchreest, PhD Email: [email protected]

Secretary 2015 Tel: 205.581.2391

Wafa A. Harrouk, PhD Email: [email protected]

Treasurer 2016 Tel: 301.796.0908

Ludmila Bakhireva, MD, PhD, MPH Email: [email protected]

Councilor 2016 Tel: 505.272.2545

COMMUNICATIONS WORKING GROUP (AD HOC) Christine Perdan Curran, PhD Email: [email protected]

Chair Tel: 859.572.6914

Christina M. Carruthers, PhD Email: [email protected]

Tel: 201.427.8034

Christina D. Chambers, PhD, MPH Email: [email protected]

Stephen B. Harris, PhD, FATS, FSB Email: [email protected]

Councilor 2015 Tel: 619.469.7886

Tel: 858.246.1704

Sarah Gloria Obican, MD Email: [email protected]

Councilor 2017 Tel: 561.289.2415

Christopher Lau, PhD Email: [email protected]

Public Affairs Committee Chair Tel: 919.541.5097

Robert G. Ellis-Hutchings, PhD Email: [email protected] Tel: 989.636.1928 Norbert Makori, PhD, MSc, BVM Email: [email protected] Tel: 425.737.5698 Anthony R. Scialli, MD Email: [email protected] Tel: 703.647.4178

Norbert Makori, PhD, MSc, BVM Publications Committee Chair Email: [email protected] Tel: 425.737.5698

EDUCATION COMMITTEE

Kary Ellen Thompson, PhD Email: [email protected] Tel: 732.227.5014

Janet R. Hardy, PhD, MSc, MPH Email: [email protected]

Chair Tel: 508.736.7722

Tacey E.K. White, PhD Email: [email protected]

Chris J. Stodgell, PhD Email: [email protected]

Secretary Tel: 585.275.1902

Kimberly Brannen, PhD Email: [email protected]

2017 Tel: 267.532.3870

Julia M. Gohlke, PhD Email: [email protected]

2016 Tel: 205.934.7060

Carolyn Kapron, PhD Email: [email protected]

Tel: 267.216.7470 Education Committee Representative Tel: 705.748.1011 (7641)

Pragati Sawhney Coder, PhD, DABT Email: [email protected]

Web Site Committee Liaison Tel: 614.642.5235

Sarah Gloria Obican, MD Email: [email protected]

Council Liaison Tel: 561.289.2415

Jane Stewart, PhD Email: [email protected]

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

Belen Tornesi, DVM, MS Email: [email protected]

Birth Defects Research (Part A) 103:311–347 (2015)

2015 Tel: 44 1625 513209 2017 Tel: 847.937.8934

TERATOLOGY SOCIETY PROGRAM

317

COMMITTEES (continued) Michelle Carll Helms, MSc Email: [email protected]

Ad Hoc, Student Tel: 856.981.3124

Linda G. Roberts, PhD, DABT Email: [email protected]

Past Chair Tel: 925.842.5381

Amy L. Inselman, PhD Email: [email protected]

Ad Hoc Tel: 870.543.7623

Eve Mylchreest, PhD Email: [email protected]

Council Liaison Tel: 205.581.2391

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

Carolyn Kapron, PhD Email: [email protected]

Past Chair Tel: 705.748.1011 (7641)

Tacey E.K. White, PhD Email: [email protected]

Council Liaison Tel: 267.216.7470

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

FASEB REPRESENTATION Belen Tornesi, DVM, MS Email: [email protected] Wafa A. Harrouk, PhD Email: [email protected]

Board Representative Tel: 847.937.8934 Science Policy Committee Tel: 301.796.0908

FINANCE COMMITTEE

NOMINATIONS AND ELECTIONS COMMITTEE Eias Zahalka, PhD, MBA Email: [email protected]

Chair Tel: 301.796.7065

George P. Daston, PhD Email: [email protected]

Tel: 513.622.3081

Jan M. Friedman, MD, PhD Email: [email protected] Susan L. Makris, MS Email: [email protected]

Tel: 703.347.8522

Jane F. Rasco, PhD Email: [email protected]

Tel: 205.348.7623

Michael G. Narotsky, PhD Email: [email protected]

Past Chair Tel: 919.541.0591

Wafa A. Harrouk, PhD Email: [email protected]

Chair Tel: 301.796.0908

Ida M. Washington, DVM, PhD, DACLAM Email: [email protected]

Past Treasurer Tel: 480.965.4386

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

Tacey E.K. White, PhD Email: [email protected]

Tacey E.K. White, PhD Email: [email protected]

Vice President Tel: 267.216.7470

Jan M. Friedman, MD, PhD Email: [email protected]

Heather Carskaddan Email: [email protected]

Executive Director Tel: 703.438.3104

MEMBERSHIP COMMITTEE Kary Ellen Thompson, PhD Email: [email protected]

Chair Tel: 732.227.5014

Mary L. Hixon, PhD Email: [email protected]

Vice Chair Tel: 617.395.5560

Elise Madison Lewis, PhD Email: [email protected]

2017 Tel: 215.443.8710

Nisha S. Sipes, PhD Email: [email protected]

2017 Tel: 919.541.0103

Sandra L. Wood, PhD Email: [email protected]

2016 Tel: 215.652.6334

Peixin Yang, PhD Email: [email protected]

2015 Tel: 410.706.8402

Russell S. Kirby, PhD, MS, FACE Email: [email protected]

Ad Hoc Tel: 813.396.2347

Jane F. Rasco, PhD Email: [email protected]

Ad Hoc Tel: 205.348.7623

Michelle Gurrola-Gal Email: [email protected]

Ad Hoc, Student Tel: 267.532.3781

Tel: 604.875.2000 (5623)

PROGRAM COMMITTEE Chair Tel: 267.216.7470 Tel: 604.875.2000 (5623)

Barbara F. Hales, PhD Email: [email protected]

Tel: 514.398.3610

Stephen B. Harris, PhD, FATS, FSB Email: [email protected]

Tel: 619.469.7886

Susan Bielmeier Laffan, PhD Email: [email protected]

Tel: 610.270.7625

Sonja A. Rasmussen, MD, MS Email: [email protected]

Tel: 404.498.1829

Kary Ellen Thompson, PhD Email: [email protected]

Tel: 732.227.5014

Janet R. Hardy, PhD, MSc, MPH Email: [email protected] Christopher Lau, PhD Email: [email protected]

Education Committee Chair Tel: 508.736.7722 Public Affairs Committee Chair Tel: 919.541.5097

Norbert Makori, PhD, MSc, BVM Publications Committee Chair Email: [email protected] Tel: 425.737.5698 John M. DeSesso, PhD Email: [email protected]

Science Committee Rep Tel: 571.227.7261

Jason M. Hansen, PhD Email: [email protected]

Student Affairs Committee Tel: 801.422.2158

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

Birth Defects Research (Part A) 103:311–347 (2015)

318

TERATOLOGY SOCIETY PROGRAM

COMMITTEES (continued) Anna Pupco, MD Email: [email protected]

OTIS Organizer Tel: 416.813.7654 (4928)

Smitha K. Infante, PhD Email: [email protected]

Ad Hoc Tel: 956-455-1820

Lori L. Driscoll, PhD Email: [email protected]

NBTS Organizer Tel: 719.227.8201

Gloria D. Jahnke, DVM, MS, DABT Email: [email protected]

Ad Hoc Tel: 919.541.3376

Alfred N. Romeo, RN, PhD Email: [email protected]

OTIS Organizer Tel: 801.584.8535

Carl L. Keen, PhD Email: [email protected]

Ad Hoc Tel: 530.681.2047

Susan L. Makris, MS Email: [email protected]

Ad Hoc Tel: 703.347.8522

Elizabeth Wasternack OTIS Organizer Email: [email protected]  Tel: 615.649.3082

CME PROGRAM COMMITTEE (AD HOC) Barbara F. Hales, PhD Email: [email protected] Jan M. Friedman, MD, PhD Email: [email protected]

Chair Tel: 514.398.3610 Tel: 604.875.2000 (5623)

Christopher Lau, PhD Email: [email protected]

Tel: 919.541.5097

Sonja A. Rasmussen, MD, MS Email: [email protected]

Tel: 404.498.1829

Mary Alice Smith, PhD Email: [email protected]

Tel: 706.542.1599

Ad Hoc Tel: 97 2267 58329

John M. Rogers, PhD Email: [email protected]

Ad Hoc Tel: 919.541.5177

Anthony R. Scialli, MD Email: [email protected]

Ad Hoc Tel: 703.647.4178

Kristin R. Di Bona, PhD Email: [email protected]

Ad Hoc, Postdoc Tel: 205.239.0219

Susanna H. Wegner, BA Email: [email protected]

Ad Hoc, Postdoc Tel: 503.467.6175

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

PUBLICATIONS COMMITTEE

PUBLIC AFFAIRS COMMITTEE Christopher Lau, PhD Email: [email protected]

Chair Tel: 919.541.5097

Marlissa A. Campbell, PhD Email: [email protected]

2017 Tel: 510.622.3190

Suzan L. Carmichael, PhD Email: [email protected]

2015 Tel: 650-736-0735

Deborah K. Hansen, PhD Email: [email protected]

2016 Tel: 870.543.7480

Kembra Lynne Howdeshell, PhD Email: [email protected]

2017 Tel: 919.316.4708

E. Sid Hunter III, PhD Email: [email protected]

2016 Tel: 919.541.3490

Susan Laessig, PhD Email: [email protected]

2016 Tel: 202.564.5232

Sarah Gloria Obican, MD Email: [email protected]

2015 Tel: 561.289.2415

Linda G. Roberts, PhD, DABT Email: [email protected]

2017 Tel: 925.842.5381

Michael A. Schellpfeffer, MD, MS Email: [email protected]

2016 Tel: 262.658.2133

Evi Struble, PhD Email: [email protected]

2015 Tel: 240.402.7403

Janet Uriu-Adams, PhD Email: [email protected]

2017 Tel: 530.752.4658

Daniel T. Wilson, PhD, DABT Email: [email protected]

2015 Tel: 908.981.3284

Connie L. Chen, PhD, MPH Email: [email protected]

Asher Ornoy, MD Email: [email protected]

Ad Hoc Tel: 202.659.3306 (131)

Birth Defects Research (Part A) 103:311–347 (2015)

Norbert Makori, PhD, MSc, BVM Email: [email protected]

Chair Tel: 425.737.5698

Melissa J. Beck, PhD Email: [email protected]

2016 Tel: 937.766.7402

Christopher J. Bowman, PhD, DABT Email: [email protected]

2017 Tel: 860.686.2361

Paul B. Bushdid, PhD Email: [email protected]

2018 Tel: 610.270.7964

Brian Enright, PhD, DABT Email: [email protected]

2018 Tel: 847.935.8778

Terry C. Hrubec, DVM, PhD Email: [email protected]

2015 Tel: 540.231.1702

Russell S. Kirby, PhD, MS, FACE Email: [email protected]

2017 Tel: 813.396.2347

Lori E. Kotch, PhD Email: [email protected]

2015

Sarah N. Mattson, PhD Email: [email protected]

2016 Tel: 619.594.7228

L. David Wise, PhD Email: [email protected]

Past Chair Tel: 610.804.5117

Michel Vekemans, MD, PhD Email: [email protected]

BDRA Editor Tel: 33 1444 94981

George P. Daston, PhD Email: [email protected]

BDRB Editor Tel: 513.622.3081

Rocky S. Tuan, PhD Email: [email protected]

BDRC Editor Tel: 412.648.2603

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

TERATOLOGY SOCIETY PROGRAM

319

COMMITTEES (continued) Allyn Molina Email: [email protected]

Wiley Representative Tel: 201.748.7656

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

SCIENCE COMMITTEE

WEB SITE COMMITTEE

George P. Daston, PhD Email: [email protected]

Tel: 513.622.3081

Pragati Sawhney Coder, PhD, DABT Email: [email protected]

Chair Tel: 614.642.5235

John M. DeSesso, PhD Email: [email protected]

Tel: 571.227.7261

Christine Perdan Curran, PhD Email: [email protected]

Vice Chair Tel: 859.572.6914

James L. Mills, MD Email: [email protected]

Tel: 301.496.5394

Jeffrey H. Charlap, MS Email: [email protected]

2017 Tel: 419.289.8700

Christina D. Chambers, PhD, MPH Email: [email protected]

Past Chair Tel: 858.246.1704

Wafa A. Harrouk, PhD Email: [email protected]

2016 Tel: 301.796.0908

Richard H. Finnell, PhD Email: [email protected]

Council Liaison Tel: 512.495.3001

Winnie Jeng, PhD, DABT Email: [email protected]

2016 Tel: 908.981.3556

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

Seyed Adel Moallem, PharmD, PhD Email: [email protected]

STUDENT AFFAIRS COMMITTEE Jason M. Hansen, PhD Email: [email protected]

Chair Tel: 801.422.2158

Dana L. Shuey, PhD, DABT Email: [email protected]

2016 Tel: 302.498.5721

Bhavesh Ahir, PhD Email: [email protected]

Ad Hoc Tel: 919.541.4438

Christina M. Carruthers, PhD Email: [email protected]

Past Chair Tel: 201.427.8034

Stephen B. Harris, PhD, FATS, FSB Email: [email protected]

Council Liaison Tel: 619.469.7886

Rahat Wadhwa Desai Email: [email protected] Robert M. Parker, PhD, DABT Email: [email protected]

2015 Tel: 98 915 509 0106 Ad Hoc, Student Tel: 706.542.1599 Past Chair Tel: 732.873.2550 (2389)

Elaine Z. Francis, PhD Email: [email protected]

Council Liaison Tel: 609.822.0217

Mary Alice Smith, PhD Email: [email protected]

President Tel: 706.542.1599

Heather Carskaddan Email: [email protected]

Executive Director Tel: 703.438.3104

Members interested in serving on a committee should contact the leadership or staff at [email protected]

Birth Defects Research (Part A) 103:311–347 (2015)

320

TERATOLOGY SOCIETY PROGRAM

2015 Sustaining Members (as of March 27, 2015)

The Teratology Society thanks the following Sponsors: PLATINUM

Charles River Scialli Consulting LLC WIL Research GOLD

AbbVie Inc. Chevron Corporation Reproductive Toxicology Center SILVER

Eli Lilly and Company Experimur Huntingdon Life Sciences/ Harlan Laboratories SNBL USA, Ltd. The J&J Pharma R&D Companies

Birth Defects Research (Part A) 103:311–347 (2015)

TERATOLOGY SOCIETY PROGRAM

321

2015 Annual Meeting Sponsors (as of March 27, 2015)

The Teratology Society thanks the following Sponsors: PLATINUM Birth Defects Center, University of Louisville Charles River CropLife America CropLife Canada ILSI HESI Developmental and Reproductive Toxicology (DART) Technical Committee March of Dimes Foundation WIL Research

Wiley-Blackwell GOLD Elsevier Exponent, Inc. Pfizer Inc.

Southern Research Institute SILVER Bristol-Myers Squibb Sandcastle Toxicology Associates Sanofi US Inc.

Society of Toxicology CONTRIBUTOR Stephen B. Harris Group

Birth Defects Research (Part A) 103:311–347 (2015)

322

TERATOLOGY SOCIETY PROGRAM

General Information

Teratology Society Booth

The Teratology Society is pleased to be able to hold our Annual Meeting concurrently with the Annual Meetings of the Neurobehavioral Teratology Society (NBTS) and Organization of Teratology Information Specialists (OTIS), allowing for joint sessions and the opportunity for networking between attendees. In addition, International Neurotoxicology Association (INA) will be meeting jointly with NBTS during the 2015 meeting.

Registration The Teratology Society Annual Meeting registration desk is located at the bottom of the escalators on the Premier Level. Hours: Friday, June 26  Saturday, June 27  Sunday, June 28  Monday, June 29  Tuesday, June 30  Wednesday, July 1 

 3:00 PM–6:00 PM  7:00 AM–6:00 PM  7:00 AM–6:00 PM  7:00 AM–6:00 PM   7:00 AM–6:00 PM  8:00 AM–2:00 PM

What Does the Meeting Registration Fee Cover? The Teratology Society Annual Meeting registration fee covers a number of food and beverage functions as well as the administrative costs for the meeting. The functions include: • • • •

Welcome Reception on Sunday Seven beverage breaks Two light receptions during poster sessions One Student/Postdoctoral Fellow Lunch Workshops (Trainees only) • Student/Postdoctoral Fellow Career Event (Trainees only) • Warkany Tea on Wednesday • Banquet on Wednesday For meals on your own, there are two dining options within the hotel. There are also several restaurants within walking distance or a short taxi ride. More information about area restaurants can be obtained from the hotel concierge.

Birth Defects Research (Part A) 103:311–347 (2015)

Come test your knowledge of our field at the Teratology Society booth. There will be different games each night including prizes and many laughs to be shared as you put your teratology trivia to the test. While you are there, find out more information about the Society and membership.

Hotel Map To assist you in locating the registration desk, meeting rooms, and Exhibit Hall there is a map of the Hôtel Bonaventure Montréal located on page 335.

Spouse/Guest Meet-and-Greet The Spouse/Guest Meet-and-Greet event is a great opportunity to meet fellow travelers, touch base with past friends, and coordinate your plans for exploring everything that Montréal has to offer. Please join us at 10:00 am on Sunday, June 28 in the Pointe-aux-Tremble room at the Hôtel Bonaventure Montréal. The event will provide an opportunity for you to ask the hotel’s concierge and Montréal tour guides (provided by the Montréal Convention and Visitors Bureau) their suggestions for must-see attractions in Montréal or have them answer any questions you may have about the city and its history. This event is free and open to guests of all registered attendees.

Photography and Recording Policy Photography, video, and/or audio recording of scientific presentations is prohibited without advance specific consent of the presenter(s)/author(s). Session chairs are asked to strictly enforce this policy, and individuals who do not comply will be asked to leave the session. In addition, cameras and recording devices are prohibited in the Exhibit Hall. Teratology Society Annual Meeting registrants grant the Teratology Society permission to reproduce, copy, and publish photographs taken at the Annual Meeting unless written notification by the registrant, stating otherwise, is submitted to the Teratology Society headquarters office prior to the Annual Meeting or while registering onsite.

First Aid and Security The Hôtel Bonaventure Montréal has house phones located throughout the hotel for use in case of an emergency. If you need medical or security assistance pick up the house phone and dial 0. The hotel operator will connect you to the correct department.

TERATOLOGY SOCIETY PROGRAM

AWARDS/LECTURES Narsingh Agnish Fellowship This award recognizes Narsingh Agnish’s contributions to the Teratology Society, particularly the implementation of the Education Course. The Narsingh Agnish Fellowship is awarded to a senior member of the Teratology Society who has made a major contribution to education in the field of teratology or a related discipline. The 2015 recipient is Melissa S. Tassinari, US Food and Drug Administration, who will present on Saturday, June 27 at 8:10 am.

Josef Warkany Lecturer This lecture recognizes Josef Warkany’s contributions to the Teratology Society. Dr. Warkany was the first person to demonstrate that exposures to environmental chemicals are responsible for production of congenital malformation. His early studies culminated in the formulation of the scientific principles of teratology. This award recognizes a scientist who has significantly contributed to the field of teratology over his/her career. This year’s lecture will be presented by William Slikker Jr., National Center for Toxicological Research, US FDA on Sunday, June 28 at 8:15 am.

F. Clarke Fraser New Investigator Award This award honors F. Clarke Fraser, one of the founding members of the Teratology Society, for his many contributions to the field of developmental toxicology. The award recipient must be an active member of the Teratology Society with evidence of a successful independent research career in birth defects research. This year’s award recipient is Sarah G. Obican, Columbia University, who will present on Sunday, June 28 at 1:30 pm.

323

Patricia Rodier Mid-Career Award in Research and Mentoring This award honors the legacy of Dr. Patricia Rodier, a past President of the Neurobehavioral Teratology Society and a Council member of the Teratology Society. The purpose of the award is to recognize a mid-career individual who has demonstrated successful independent research in neurobehavioral teratology, birth defects, or other related fields involving the central nervous system; and has demonstrated a commitment to mentorship of students, postdoctoral fellows, young investigators, and/or trainees. This year’s award recipient is Gregg D. Stanwood, Florida State University, who will present on Sunday, June 28 at 5:30 pm.

Birth Defects Research Distinguished Scholar Awards These awards recognize distinguished authors for the importance, impact, and relevance of their published works in the field of birth defects research. The dual purpose of these awards is to provide recognition to the authors of high impact papers and to encourage authors trained in various disciplines to submit high quality papers to Birth Defects Research Part A and Birth Defects Research Part B. Award recipients will be recognized during the Annual Meeting Banquet on Wednesday, July 1.

Birth Defects Research Part A The 2015 recipients of this award are Mark A. Canfield, Texas Department of State Health Services; Adolfo Correa, University of Mississippi Medical Center; and Russell S. Kirby, University of South Florida for their research associated with national prevalence estimates for selected birth defects (reference papers: National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001; BDRA 76, 11: 747–756; and Updated national birth prevalence estimates for selected birth defects in the United States, 2004-2006; BDRA 88, 12: 1008-1016).

James G. Wilson  Publication Award This award is presented in recognition of the best paper accepted or published in the journal Birth Defects Research. The dual purpose of the award is to provide recognition to the authors of the best paper and to encourage authors trained in various disciplines to submit high-quality papers to Birth Defects Research. The paper selected for this year’s award is The Microbiome in Early Life: Self-Completion and Microbiota Protection As Health Priorities. Rodney R. Dietert, Cornell University, will present the data on Sunday, June 28 at 2:00 pm.

Mark A. Canfield

Adolfo Correa

Russell S. Kirby

Birth Defects Research (Part A) 103:311–347 (2015)

324

TERATOLOGY SOCIETY PROGRAM

Birth Defects Research Part B

Silent Auction

The 2015 recipients of this award are Karen A. Augustine-Rauch, BristolMyers Squibb and Kimberly Brannen, Charles River Laboratories for their research associated with development of a zebrafish embryo teratogenicity assay and the associated quantitative prediction model (reference paper: Development of a zebrafish embryo teratogenicity assay and quantitative predictive model; BDRB Karen A. Kimberly Brannen 89, 1: 66–77). Augustine-Rauch

The Teratology Society is holding a Silent Auction during the Welcome Reception on Sunday, June 28. Bidding will start at 6:00 pm and will conclude at 7:30 pm. A list of the highest bidders will be posted in the registration area by Monday at 12:00 noon. All items must be claimed by Wednesday at 12:00 noon. The Society is unable to ship auction items to the highest bidder; unclaimed items will become property of the Society. Your generosity will help us continue our mission to support the activities of our graduate students and postdoctoral fellows.

Robert L. Brent Lecture This lecture recognizes Robert L. Brent’s contributions to the Teratology Society and particularly to the implementation of the “Teratogen Update.” The purpose of the Robert L. Brent Lecture is to facilitate the discussion of new and old teratogens during the Annual Meeting. The 2015 Robert L. Brent Lecture will be presented by Jan M. Friedman, University of British Columbia, on Tuesday, June 30 at 8:30 am.

Edward W. Carney Distinguished Service Award This award honors Edward W. Carney, Past President of the Teratology Society, for his exemplary dedication and service to the Society and the field of teratology. The 2015 Edward W. Carney Distinguished Service Award recipient is Jan M. Friedman, University of British Columbia. Dr. Friedman has had a wide reaching impact on the Teratology Society stemming from his nearly 30 years of membership and service to our Society, his active role in seven committees/focus areas, and his service as the Society’s President. The personal impact he has had on our field is clear as he is known to many as a consummate scientist, a trusted advisor, and an outstanding teacher and mentor to numerous students, fellows, and current members. Beyond being well respected internationally and with an exemplary publication record, his advisory roles to TERIS, the US FDA, and the CDC stand out as an example of his strong leadership within our field. In summary, through these and other numerous contributions he has left an indelible mark on the Teratology Society and the field of birth defects research at large.

HIGHLIGHTS Welcome Reception The Welcome Reception will be held in Fontaine B on Sunday, June 28 at 6:00 pm. The reception is open to registered attendees of the Teratology Society, INA, and NBTS Annual Meetings. Please wear your badge to gain entrance to the reception.

Birth Defects Research (Part A) 103:311–347 (2015)

Exhibits Exhibits will be open in Fontaine B to attendees Sunday through Tuesday in the evenings and will feature companies offering teratologyrelated products and services. Scientific posters will be displayed in the Exhibit Hall on Monday and Tuesday. Although the Exhibit Hall will be open and posters on display Sunday afternoon through Tuesday evening, the exhibits will be attended only during the times listed below.

Exhibits Attended

Sunday, June 28  Monday, June 29  Tuesday, June 30 

 6:00 PM–7:30 PM  5:30 PM–7:30 PM  6:00 PM–8:00 PM

Poster Sessions The Poster Sessions will be held in Fontaine B on Monday, June 29 and Tuesday, June 30. The Teratology Society, INA, NBTS, and OTIS Joint Poster Session 1 will take place on Monday. The posters for this session will be on display starting at 12:30 pm. The authors will be present for discussion from 5:30 pm–7:30 pm. Poster Session 2 will take place on Tuesday. The posters for this session will be on display starting at 12:30 pm. The authors will be present for discussion from 6:00 pm–8:00 pm.

Banquet and Award Presentations The Banquet will be held on Wednesday, July 1. The reception (cash bar) will be held in the Montréal Ballroom Foyer beginning at 6:30 pm. Dinner will be served at 7:30 pm in Outremont. Banquet tickets are required for this event. The tickets are included in your registration materials and are not transferable. Guest tickets may be purchased at the registration desk until 12:00 noon on Monday, June 29. Teratology Society Awards recognized during the banquet are as follows:

Travel Awards James C. Bradford Memorial Student Poster Award Wilson Presentation Awards Marie W. Taubeneck Award Birth Defects Research Distinguished Scholar Awards Edward W. Carney Distinguished Service Award Recognition of Other Awards Presented Throughout the Week

TERATOLOGY SOCIETY PROGRAM

34 Years of Volleyball Come one, come all, and join the fun! The 34th Annual Volleyball Game is scheduled for Wednesday, July 1 from 6:30 am–7:30 am at the Parc Jeanne-Mance located at 3555 St-Urbain, Montréal, QC. This is an event that you will not want to miss. Stop by the registration desk for more information on how to participate in this match—it is free and open to all attendees. If you don’t play, come out and cheer!

Student/Postdoctoral Fellow Activities Special events for student and postdoctoral attendees will occur throughout the Teratology Society meeting. These events were planned with you in mind and allow you to meet other students, postdoctoral fellows, and scientists in the field. The following special events are scheduled. Saturday Mixer—Come get acquainted or reacquainted with your fellow student and postdoctoral attendees before the start of the meeting. Students and postdoctoral attendees are encouraged to meet at Le Belvedere at 5:30 pm on Saturday, June 27. Student/Postdoc Treasure Hunt—At this year’s Annual Meeting, the students and postdocs are encouraged to participate in the second annual Teratology Society Treasure Hunt. This activity is intended to facilitate networking between the students/postdocs and the established Society members at the Annual Meeting. A list of tasks will be available at the registration desk. All students/postdocs who complete the list will receive a prize, and there will be a random drawing for all participants who complete at least half of the list (two chances for those who complete all tasks) for a grand prize of $100. The drawing will take place at the Teratology Society Banquet. All who participate are winners, but you must be present to collect a prize. Tasks will include

325

interacting with various members and participating in activities over the course of the meeting. Consider the experience a human treasure hunt. It is a great opportunity to discuss your research, connect with members and attendees, learn about different career paths, and forge relationships that you will “treasure” throughout your career! Student/Postdoctoral Fellow Platform Session: Wilson Presentation Award Competition—This year’s Student/Postdoctoral Platform Session showcases the work of ten students and postdoctoral fellows. The participants in this session were selected by the Student Affairs Committee from submitted abstracts. The presenters in this session will compete for the Wilson Presentation Award. This award was established in honor of James G. Wilson, one of the founding members of the Teratology Society and recognizes the work of students and postdoctoral fellows in the field of teratology. It is awarded based on the content and quality of the oral presentations. The two award recipients will be announced during the Teratology Society Banquet on Wednesday, July 1. Make plans to support the Society’s student and postdoctoral members by attending this session on Sunday, June 28 at 9:00 am. Dine with a Teratology Ambassador—The Dine with a Teratology Ambassador program is a special opportunity for students and postdoctoral fellows to meet with Associate and Regular members of the Society while enjoying a light breakfast. This event will take place on Sunday, June 28 from 7:00 am until 8:00 am. Advance signup is required. Please stop by the registration desk for more information. Teratology Society and MARTA Student Career Event—Take advantage of this great networking opportunity! Join the Middle Atlantic Reproduction and Teratology Association (MARTA) and the Teratology Society for dinner and conversation at a Student Career Event in Salon Le Castillon on Monday, June 29 from 7:30 pm–10:00 pm. This popular event is for students and postdoctoral fellows attending the joint meetings of the Teratology Society, INA, NBTS, and OTIS. As you prepare for the next phase in your professional career, we offer you this opportunity to meet with other students and postdoctoral fellows and to interact with scientists from academia, government, and industry. This is also an opportunity for you to discuss your future and the various career paths available to you. James C. Bradford Memorial Student Poster Award—This is an award for the best poster presentation by a student at the Annual Meetings of the Teratology Society, INA, NBTS, and OTIS. It is jointly sponsored by MARTA and Sanofi US. The award will be announced during the Teratology Society Banquet.

Birth Defects Research (Part A) 103:311–347 (2015)

326

TERATOLOGY SOCIETY PROGRAM

HÔTEL BONAVENTURE MONTRÉAL

GROUND TRANSPORTATION

Conference Site

(All prices are subject to change.)

In the heart of downtown Montréal, Québec, Canada stands the Hôtel Bonaventure Montréal. This unique downtown Montréal hotel offers warm hospitality and exceptional services suited to please guests traveling for many purposes. Located opposite Montréal Central train station (with an indoor path for easy access) and above Bonaventure metro station, the Hôtel Bonaventure is steps away from major attractions, the business district, and public transportation convenient for all guests.

The Montréal-Pierre Elliott Trudeau (YUL) International Airport is located approximately 20 miles from the Hôtel Bonaventure Montréal. Transportation options include taxis and the express bus.

The Hôtel Bonaventure offers several dining options: Le Castillon, an award-winning restaurant serving breakfast, lunch, and dinner; Le Belvedere, a bistro bar open for lunch, dinner, and cocktails; and Bar Soleil, offering summer poolside dining; and room service.

Business Center The Hôtel Bonaventure Montréal has a full-service business center open 24 hours a day, 7 days a week. There are two Macintosh computers and one PC available for hotel guests, and printing is free of charge.

Printing Your Boarding Pass Boarding passes can be printed in the Hôtel Bonaventure Montréal Business Center.

Internet Access The Teratology Society understands the importance of staying connected while you are away. The Teratology Society will have an Internet Café located in the registration area which will be available during registration hours. The café will include several computers with Internet service. Please note that wireless access is not available in the Internet Café, in the meeting rooms, or in the meeting room foyers. The Hôtel Bonaventure Montréal offers complimentary wireless Internet access in sleeping rooms and the lobby area for those who are in the Teratology Society room block.

Taxi You can get a taxi or limousine at the arrivals level near the central exit located in front of the cloakroom, where a dispatcher will assist you. No reservation is required. All taxi and limousine operators working out of Montréal–Trudeau are required to have a permit and to comply with its terms and conditions. Occasionally, during periods of excessive demand, Aéroports de Montréal may call an outside operator. Taxi fares are by meter for all other destinations except downtown. Payment methods: Visa, MasterCard, and American Express credit cards are accepted. Some drivers accept US currency, but provincial regulations require customers to pay in Canadian currency, the minimum fare is $17 CAD. The approximate taxi fee from the airport to the hotel is $40 CAD.

Express Bus The Société de transport de Montréal (STM) runs an express bus line (747) between the airport and downtown. The 747 line uses only low-floor buses and is in service 24 hours a day, 7 days a week. Buses are equipped with luggage racks. The trip will take around 25–35 minutes depending on traffic. Use the stop at the corner of Mansfield and RenéLévesque for the hotel; it is one block north of the hotel. Fare cards can be purchased at the airport (international arrivals level), in every metro station, and at the Gare d’autocars de Montréal (central bus terminal). The fare for a one-way trip is priced at $10 CAD.

Hotel Parking The Hôtel Bonaventure Montréal offers self-parking for $21 CAD per day or valet parking for $29 CAD per day including in and out privileges.

Future Annual Meetings 56th Annual Meeting

57th Annual Meeting

58th Annual Meeting

Grand Hyatt San Antonio San Antonio, Texas June 25–29, 2016

Grand Hyatt Denver Denver, Colorado June 24–28, 2017

Hilton Clearwater Clearwater, Florida June 23–27, 2018

Birth Defects Research (Part A) 103:311–347 (2015)

TERATOLOGY SOCIETY PROGRAM

327

Hôtel Bonaventure Montréal Maps

Premier Level

(use down escalator)

Exhibits and Posters

Fontaine Fontaine Fontaine Fontaine E F G H

Fontaine B Entrance

Frontenac Escalator

Teratology Society Registration

OTIS

Mont-Royal

Teratology Society Westmount

Fundy Speaker Ready Room

Longueuil

Pointe Jacques Aux Trembles Cartier

St. Pierre

St. St. St. Laurent Michel Léonard

NBTS

Outremont

INA

Verdun

Birth Defects Research (Part A) 103:311–347 (2015)

328

TERATOLOGY SOCIETY PROGRAM

Program Agenda FRIDAY, JUNE 26, 2015



3:00 PM–6:00 PM REGISTRATION OPEN—Registration Desk



3:00 PM–6:00 PM SPEAKER READY ROOM OPEN—St. Lambert



6:00 PM–9:00 PM COUNCIL 1A MEETING—Fontaine H SATURDAY, JUNE 27, 2015



7:00 AM–6:00 PM REGISTRATION OPEN—Registration Desk



7:00 AM–6:00 PM SPEAKER READY ROOM OPEN—St. Lambert



7:30 AM–8:00 AM EDUCATION COURSE COFFEE AND CONTINENTAL BREAKFAST—Westmount

8:00 AM–12:00 Noon EDUCATION COURSE SESSION 1 (Separate Registration Required)—Westmount Occupational and Environmental Exposures: Reproductive and Developmental Hazards in the Workplace and Home Organized by the Education Committee, Chairperson, Janet Hardy, ECC Population Health

8:00 AM–8:10 AM



8:10 AM–8:40 AM



8:40 AM–8:45 AM



8:45 AM–9:30 AM



9:30 AM–10:15 AM



10:15 AM–10:30 AM

Break



10:30 AM–11:15 AM



11:15 AM–12:00 Noon

Postnatal Exposures: Truths and Myths of Occupational and Environmental Hazards in Human Milk Ruth A. Lawrence, University of Rochester Medical Center How to Evaluate Workplace, Environmental, and Home Exposures and Their Risks during Pregnancy Richard K. Miller, University of Rochester Medical Center

Birth Defects Research (Part A) 103:311–347 (2015)

Welcome Teratology Society President Mary Alice Smith, University of Georgia Narsingh Agnish Fellow Lecture Melissa S. Tassinari, US Food and Drug Administration Course Overview Education Committee Chairperson, Janet Hardy, ECC Population Health Overview of Occupational and Environmental Teratogenic Exposures, Prepregnancy through Childhood Jonathan Chevrier, McGill University Global Regulatory Guidelines and Risk Assessment for Occupational and Environmental Hazards Elaine Z. Francis, Sandcastle Toxicology and Alan M. Hoberman, Charles River

TERATOLOGY SOCIETY PROGRAM

329

SATURDAY/SUNDAY

12:00 Noon–1:30 PM LUNCH ON YOUR OWN 12:00 Noon–1:30 PM STUDENT AFFAIRS COMMITTEE MEETING—Fontaine H

1:30 PM–5:00 PM EDUCATION COURSE SESSION 2 (Separate Registration Required)—Westmount Ethics and Ethical Implications

Organized by the Education Committee, Chairperson, Janet Hardy, ECC Population Health

1:30 PM–1:35 PM

Course Overview Education Committee, Chairperson, Janet Hardy, ECC Population Health Fundamentals of Ethics in Research Bernard Robaire, McGill University Procurement of Reproductive Goods and Services for Research, Clinical, or Individual Purposes I. Glenn Cohen, Harvard Law School



1:35 PM–2:20 PM



2:20 PM–3:05 PM



3:05 PM–3:20 PM

Break



3:20 PM–4:05 PM



4:05 PM–4:50 PM



4:50 PM–5:00 PM

Ethical and Social Implications of Prenatal Testing and the Challenge of Noninvasive Prenatal Testing Vardit Ravitsky, Université de Montréal Ethical Decision-Making regarding Preterm and Small-forGestational-Age Babies Annie Janvier, Université de Montréal Discussion



5:30 PM–7:30 PM STUDENT AND POSTDOCTORAL FELLOW MIXER—Le Belvedere



6:30 PM–9:30 PM COUNCIL 1B MEETING, COMMITTEE REPORTS, AND LEADERSHIP TRAINING—Fontaine H SUNDAY, JUNE 28, 2015



7:00 AM–6:00 PM REGISTRATION OPEN—Registration Desk



7:00 AM–6:00 PM SPEAKER READY ROOM OPEN—St. Lambert



7:00 AM–8:00 AM DINE WITH A TERATOLOGY SOCIETY AMBASSADOR—Fountain H



7:00 AM–8:00 AM BDRB EDITORIAL BOARD MEETING—St. Pierre



8:00 AM–8:15 AM PRESIDENT’S WELCOME—Westmount Teratology Society President, Mary Alice Smith, University of Georgia



8:15 AM–9:00 AM JOSEF WARKANY LECTURE (Joint with OTIS)—Westmount Developmental Toxicology: Putting the Puzzle Together Chairperson: Mary Alice Smith, University of Georgia

Lecturer: William Slikker Jr., National Center For Toxicological Research, US FDA

Birth Defects Research (Part A) 103:311–347 (2015)

330

TERATOLOGY SOCIETY PROGRAM

SUNDAY



9:00 AM–11:30 AM STUDENT AND POSTDOCTORAL FELLOW PLATFORM SESSION 1—Westmount Organized by the Student Affairs Committee Chairpersons: Jason M. Hansen, Brigham Young University and Stephen B. Harris, Stephen B. Harris Group Presenting author is underlined.

9:00 AM–9:15 AM



9:15 AM–9:30 AM

1



9:30 AM–9:45 AM

3



9:45 AM–10:00 AM

4



10:00 AM–10:15 AM

5



10:15 AM–10:30 AM

Break—Fontaine C



10:30 AM–10:45 AM

Impact of Maternal Overweight during Pregnancy on the Newborn Gut Microbiome Koleva PT1, Kim JS2, Guttman DS3, Sears MR4, Becker AB5, Mandhane PJ1, Subbarao P6, Turvey SE7, Scott JA2, Kozyrskyj AL1, Investigators CHILD Study8. 1Department of Pediatrics, University of Alberta, Edmonton, AB, Canada, 2Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada, 3Cell and Systems Biology, University of Toronto, Toronto, ON, Canada, 4Department of Medicine, McMaster University, Hamilton, ON, Canada, 5Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada, 6Department of Pediatrics, University of Toronto, Toronto, ON, Canada, 7Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada, 8Canadian Healthy Infant Longitudinal Development Study, Hamilton, ON, Canada.

Birth Defects Research (Part A) 103:311–347 (2015)

6

Introduction Jason M. Hansen, Brigham Young University Latent Teratogen-Induced Heart Deficits Are Unmasked Postnatally with Mathematical Analysis and Machine Learning on ECG Signals Burton T1,2, Howe-Patterson M2, Ramchandani S2, Ozolins TRS1. 1 Queen’s University, Kingston, ON, Canada, 2Analytics for Life, Kingston, ON, Canada. Zebrafish Genetic Screens Identify Ethanol Susceptibility Loci Lovely CB, Norrie JL, Henegar T, Swartz ME, Eberhart JK. University of Texas at Austin, Austin, TX, United States. The Role of p53 Signalling in Hydroxyurea Embryotoxicity El Husseini N, Hales B. McGill University, Montréal, QC, Canada. Exploring the Associations between microRNA Expression Profiles and Environmental Pollutants in Human Placenta from the National Children’s Study (NCS) Li Q1, Kappil M1, Li A2, Dassanayke PS2, Darrah T3, Friedman AE4, Friedman M4, Lambertini L1, Landrigan P1, Stodgell CJ4, Aagaard K5, Schadt E1, Murray J6, Clark EB7, Dole N8, Culhane J9, Swanson J10, Varner M7, Moye J11, Kasten C12, Miller RK4, Chen J1, National Children’s Study Consortium11. 1Ichan School of Medicine, Mt. Sinai, New York, NY, United States, 2University of Illinois, Chicago, Chicago, IL, United States, 3 Ohio State University, Columbus, OH, United States, 4University of Rochester School of Medicine and Dentistry, Rochester, NY, United States, 5 Baylor School of Medicine, Houston, TX, United States, 6University of Iowa, Iowa City, IA, United States, 7University of Utah, Salt Lake City, UT, United States, 8University of North Carolina, Chapel Hill, NC, United States, 9The Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 10University of California, Irvine, Irvine, CA, United States, 11 National Institutes of Health, Bethesda, MD, United States, 12US Food and Drug Administration, Silver Spring, MD, United States.

TERATOLOGY SOCIETY PROGRAM

331

SUNDAY



10:45 AM–11:00 AM

7



11:00 AM–11:15 AM

9



11:15 AM–11:30 AM

10

Predicting Pregnancy-Related Cases of Listeriosis through In Vitro Invasiveness and Biofilm Formation Wadhwa Desai R, Amosu M, Smith MA. University of Georgia, Athens, GA, United States. Altered Mammary Gland Development As a Result of In Utero Exposure to a High and Low Dose of Inorganic Arsenic (iAs) in the CD-1 Mouse Tucker D1,2, Chappell V2, Rodriguez K3, Yao H3, Fenton S2. 1University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 2Division of NTP, NTPL, NIEHS, Research Triangle Park, NC, United States, 3 Laboratory of Reproductive and Developmental Toxicology, DIR, NIEHS, Research Triangle Park, NC, United States. Brca1 Knockout Progeny Exhibit Enhanced In Utero Death and Ethanol- Initiated Embryonic DNA Oxidation Drake D1, Shapiro AM1, Wells PG1,2. 1Deptartment of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada, 2Department. of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

10:00 AM–10:30 AM SPOUSE AND GUEST MEET-AND-GREET—Pointe-aux-Trembles

(Open to Teratology Society, NBTS, INA, and OTIS Spouses and Guests)



11:30 AM–1:30 PM LUNCH ON YOUR OWN

12:00 Noon–1:30 PM CONSTITUTION AND BYLAWS COMMITTEE MEETING—Fundy 12:00 Noon–1:30 PM SCIENCE COMMITTEE MEETING—St. Pierre 12:00 Noon–1:30 PM STUDENT AND POSTDOCTORAL LUNCH WORKSHOP (Advance Registration Required)—Outremont

Transitioning from Graduate School, to Postdoctoral Fellow, to First Job (W1)

Chairpersons: Jeffrey H. Charlap, WIL Research and Christine P. Curran, Northern Kentucky University





12:00 Noon–12:05 PM



12:05 PM–12:25 PM



12:25 PM–12:45 PM



12:45 PM–1:05 PM



1:05 PM–1:20 PM



1:20 PM–1:30 PM

Introduction Teaching and Learning: What You Need to Know No Matter What Career Path You Take Christine P. Curran, Northern Kentucky University Good Laboratory Practices: What Are They and Why Do They Matter? Jeffrey H. Charlap, WIL Research Building a Professional Network: Comparing Social Media and “Old-School” Face-to-Face Christopher S. Sledzik, Brandmuscle Career Transitions: How to Build Bridges and Not Burn Them Nicole C. Kleinstreuer, ILS/NICEATM Discussion Niem Tu Huynh, Career Planning Service (CaPS), McGill University

1:30 PM–2:00 PM F. CLARKE FRASER NEW INVESTIGATOR AWARD—Westmount The Risk of a Broken Heart

Chairperson: Bruce K. Beyer, Sanofi US Inc. Lecturer: Sarah Gloria Obican, Columbia University

Birth Defects Research (Part A) 103:311–347 (2015)

332

TERATOLOGY SOCIETY PROGRAM

SUNDAY



2:00 PM–2:30 PM JAMES G. WILSON PUBLICATION AWARD—Westmount The Microbiome in Early Life: Self-Completion and Microbiota Protection As Health Priorities Chairperson: L. David Wise (ret.)

Lecturer: Rodney R. Dietert, Cornell University



2:30 PM–5:30 PM PATERNAL EXPOSURES IMPACT PROGENY OUTCOME BY ALTERING THE SPERM GENOME AND EPIGENOME SYMPOSIUM—Westmount Chairpersons: Barbara F. Hales and France-Helene Paradis, McGill University





2:30 PM–2:40 PM

Introduction



2:40 PM–3:15 PM

S1



3:15 PM–3:50 PM

S2

Impact of Paternal Aging on Male Germ Cells and Progeny Bernard Robaire, McGill University Paternal Lifestyle As a Source of Germline Mutations Transmitted to Offspring Francesco Marchetti, Health Canada



3:50 PM–4:05 PM

Break—Fontaine C



4:05 PM–4:40 PM

S3



4:40 PM–5:15 PM

S4



5:15 PM–5:30 PM

The Role of the Environment and the Sperm Epigenome in Development and Disease Sarah Kimmins, McGill University The Transgenerational Effects of Paternal Glucocorticoid Treatment Moshe Szyf, McGill University Discussion

2:30 PM–5:30 PM PLATFORM SESSION 2—Outremont Abnormal Neural Development

Chairpersons: Janee Gelineau-van Waes, Creighton University School of Medicine and Sarah Gloria Obican, Columbia University Presenting author is underlined.

2:30 PM–2:45 PM

Introduction



2:45 PM–3:00 PM

11



3:00 PM–3:15 PM

12



3:15 PM–3:30 PM

13

Interaction between Maternal Spontaneous Abortion and Periconceptional Folic Acid Use on NTDs Risks Pei L1, Li Z2, Ye R2, Liu J2, Ren A2. 1Institute of Population Research, Peking University, Beijing, China, 2Institute of Reproductive and Child Health, Ministry of Health Key Laboratory of Reproductive Health, Peking University, Beijing, China. Persistent Elevated Incorporated Cs-137 Levels in Pregnant Women and Blastopathy Rates in Ukraine Wertelecki W1,4, Yevtushok L2, Korblein A1, Zymak-Zakutnia N3, Komov O5, Kuznietsov I6, Lapchenko S1, Sosyniuk Z2. 1OMNI-Net for Children, Ukraine, Rivne, Ukraine, 2Rivne Province Regional Medical Diagnostic Center, Rivne, Ukraine, 3Khmelnytsky City Perinatal Center, Khmelnytsky, Ukraine, 4OMNInet–Medword LLC, Mobile, AL, United States, 5Rivne Province State Sanitary and Epidemiologic Service, Rivne, Ukraine, 6Human and Animal Physiology Department, Eastern-European University, Lutsk, Volyn, Ukraine. Traffic-Related Air Pollution, Neighborhood Socioeconomic Factors, and Neural Tube Defects in the San Joaquin Valley of California Padula AM1, Yang W1, Carmichael SL1, Tager IB2, Lurmann F3, Hammond SK2, Shaw GM1. 1Stanford University, Stanford, CA, United States, 2University of California, Berkeley, Berkeley, CA, United States, 3 Sonoma Technology, Inc., Petaluma, CA, United States.

Birth Defects Research (Part A) 103:311–347 (2015)

TERATOLOGY SOCIETY PROGRAM

333

SUNDAY





3:30 PM–3:45 PM

14

Effects of Maternal Periconceptional Sleep Quality on Risk of Neural Tube Defects Li Z1, Raynes-Greenow C2, Ren A1. 1Institute of Reproductive and Child Health, Ministry of Health Key Laboratory of Reproductive Health, Peking University, Beijing, China, 2Sydney School of Public Health, Sydney Medical School, The University of Sydney, Sydney, Australia.



3:45 PM–4:00 PM

Break—Fontaine C



4:00 PM–4:15 PM

15



4:15 PM–4:30 PM

16



4:30 PM–4:45 PM

17



4:45 PM–5:00 PM

18



5:00 PM–5:15 PM

19



5:15 PM–5:30 PM

20

Changes in the Cell Cycle and in the Neuronal Differentiation Induced by Homocysteine in the Spinal Cord of Chickens Kobus Bianchini K1, Bourckhardt GF2, Nazari EM2, Müller YMR2. 1 Universidade do Estado de Santa Catarina (UDESC), Florianópolis, SC, Brazil, 2Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil. Expression of PAX3 and P53 in Human Fetuses with Neural Tube Defects Ren AG1,2, Yi DQ1, Wang CY1, Wang LL1,2, Jin L1,2, Liu JF1,2, Zhang YL1,2. 1 Institute of Reproductive and Child Health, Peking University, Beijing, China, 2 Key Laboratory of Reproductive Health, Ministry of Health, Beijing, China. An Adverse Outcome Pathway Framework for Neural Tube and Axial Defects Mediated by Modulation of Retinoic Acid Homeostasis Piersma AH, Pennings J, Tonk ECM. RIVM, Bilthoven, Netherlands. Mitochondrial Gene Expression Profiles Are Associated with MaternalPsychosocial Stress in Pregnancy and Infant Neurodevelopment Lambertini L1, Nomura Y2,1, Chen J1. 1Icahn School of Medicine at Mount Sinai, New York, NY, United States, 2Queens College, CUNY, Flushing, NY, United States. Red Blood Cell Folate Insufficiency (RBCFI) among Nonpregnant Women of Childbearing Age (WCBA) in Guatemala 2009–2010: Predicted Risk of Neural Tube Defects (NTDs) Rosenthal J1, Ramirez N2, Lopez-Palacios E3, Sniezek J1, Vellozzi C1. 1 Centers for Disease Control and Prevention, Atlanta, GA, United States, 2 Ministry of Health, Guatemala City, Guatemala, 3World Food Program, Guatemala City, Guatemala. Global Update on the Impact of Folic Acid Fortification on Neural Tube Defects Sekkarie A1, Zaganjor I1, Tsang BL1, Cannon M1, Sniezek J1, Mulinare J2, Williams J1, Razzaghi H2, Rosenthal J1. 1NCBDDD, CDC, Atlanta, GA, United States, 2Carter Consulting, Inc, Atlanta, GA, United States.

5:30 PM–6:00 PM PATRICIA RODIER MID-CAREER AWARD IN RESEARCH AND MENTORING (Joint with NBTS)—Westmount Development Causes and Consequences of Drug Abuse (L1)

Chairpersons: Bruce K. Beyer, Sanofi US Inc. and Lori L. Driscoll, Colorado College Lecturer: Gregg D. Stanwood, Florida State University



6:00 PM–7:30 PM WELCOME RECEPTION, SILENT AUCTION, AND EXHIBITS ATTENDED (Joint with INA and NBTS)—Fontaine B



7:30 PM–8:30 PM COMMUNICATIONS WORKING GROUP MEETING—Jacques-Cartier



7:30 PM–8:30 PM PUBLICATIONS COMMITTEE MEETING—St. Pierre

Birth Defects Research (Part A) 103:311–347 (2015)

334

TERATOLOGY SOCIETY PROGRAM

MONDAY, JUNE 29, 2015



7:00 AM–6:00 PM REGISTRATION OPEN—Registration Desk



7:00 AM–6:00 PM SPEAKER READY ROOM OPEN—St. Lambert



7:00 AM–8:00 AM 2016 PROGRAM COMMITTEE MEETING—St. Pierre



8:00 AM–9:00 AM REMEMBERING F. CLARKE FRASER—Westmount Chairperson: Richard H. Finnell, The University of Texas at Austin and Michel Vekemans, Hopital Necker-Enfants Malades

8:00 AM–8:08 AM



8:08 AM–8:21 AM



8:21 AM–8:34 AM



8:34 AM–8:47 AM



8:47 AM–9:00 AM

Introduction Patrick McLeod, University of Victoria Oral Clefts Diana M. Juriloff, University of British Columbia Spectrum of Anomalies in the Meckel Syndrome: An Update Michel Vekemans, Hopital Necker-Enfants Malades Birth Defects, Imprinting, and Intergenerational Effects Jacquetta M. Trasler, McGill University Strain Differences in Susceptibility to Teratogen-Induced Neural Tube Defects Richard H. Finnell, The University of Texas at Austin

9:00 AM–12:00 Noon WILEY-BLACKWELL SYMPOSIUM—Westmount Are Human Skeletal Malformations the Result of Embryonic Arterial Dysgenesis? Chairpersons: Lewis B. Holmes, MassGeneral Hospital for Children and David R. Hootnick, SUNY Upstate Medical University

9:00 AM–9:05 AM

Introduction



9:05 AM–9:45 AM

S5



9:45 AM–10:25 AM

S6

Embryonic Arterial Dysgenesis and Long Bone Deficiencies David R. Hootnick, SUNY Upstate Medical University Anatomical Inferences regarding Gestational Stage and Location of Teratogenic Events in Malformed Human Limbs John M. DeSesso, Exponent, Inc.



10:25 AM–10:40 AM

Break—Fontaine B



10:40 AM–11:20 AM

S7



11:20 AM–12:00 Noon

S8

Patterning Limb Development Lewis Wolpert, University College, London Thalidomide-Induced Teratogenesis: Lessons and Insights into Abnormal Development Neil Vargesson, University of Aberdeen

9:00 AM–12:00 Noon REGULATORY NEURODEVELOPMENTAL TESTING: NEW GUIDING PRINCIPLES FOR HARMONIZATION OF DATA COLLECTION AND ANALYSIS WORKSHOP (Joint with NBTS)—Outremont Chairpersons: Alan M. Hoberman, Charles River and Abby A. Li, Exponent, Inc.

9:00 AM–9:10 AM W2



9:10 AM–9:35 AM W3

Birth Defects Research (Part A) 103:311–347 (2015)

Reexamining the Developmental Neurotoxicity Study and Risk Assessment Francis Bailey, Health Canada Pest Management Regulatory Agency Evaluating Data Variability for Neurobehavioral Measures: How Much Is Too Much? Larry P. Sheets, Bayer CropScience

TERATOLOGY SOCIETY PROGRAM

335

MONDAY



9:35 AM–9:55 AM W4



9:55 AM–10:20 AM W5

New Insights into Analysis of Highly Variable Data: Motor Activity As a Case Study Wayne Bowers, Health Canada and Carleton University Hypothesis-Driven Testing and Analysis: Auditory Startle As a Case Study Kathleen Raffaele, Office of Solid Waste and Emergency Response, US EPA



10:20 AM–10:35 AM

Break—Fontaine B



10:35 AM–11:00 AM W6



11:00 AM–11:25 AM W7

Standardization of SOPs to Evaluations: Impacts on Regulatory Decisions Using Learning and Memory As Case Studies Virginia C. Moser, Office of Research and Development, US EPA Weight of Evidence (WOE) and Benchmark Dose (BMD) Analysis: Brain Morphometry and Startle Behavior As Examples Abby A. Li, Exponent, Inc. Discussion Francis Bailey, Health Canada Pest Management Regulatory Agency; Alan M. Hoberman, Charles River; Angela Hofstra, Syngenta Canada; and Susan L. Makris, US Environmental Protection Agency



11:25 AM–12:00 Noon

12:00 Noon–1:30 PM LUNCH ON YOUR OWN 12:00 Noon–1:30 PM BDRA EDITORIAL BOARD—St. Pierre 12:00 Noon–1:30 PM PAST PRESIDENTS’ AND HONOREES’ LUNCHEON (By Invitation Only)—Fontaine H

1:30 PM–5:30 PM MARCH OF DIMES SYMPOSIUM (Joint with OTIS)—Westmount Perinatal Outcomes following Assisted Reproductive Technologies

Chairpersons: Kembra L. Howdeshell, National Institute of Environmental Health Sciences and Laxmi Kondapalli, Colorado Center for Reproductive Medicine



1:30 PM–1:35 PM

Introduction Kembra L. Howdeshell, National Institute of Environmental Health Sciences 1:35 PM–2:10 PM S9 The Occurrence of Birth Defects in Relation to Assisted Reproductive Technologies in the Massachusetts Outcomes Study of Assisted Reproductive Technology (MOSART) Database Kelly D. Getz, The Children’s Hospital of Philadelphia 2:10 PM–2:50 PM S10 The Impact of Multiple Gestations on IVF Outcome Barbara Luke, Michigan State University 2:50 PM–3:30 PM S11 Assisted Reproduction and Changes in the Epigenome Winifred Mak, Yale University



3:30 PM–3:45 PM



3:45 PM–4:25 PM S12 Prospective Cohort Study of Autism, Neurodevelopment, and Behavior inYoung Children Conceived by Assisted Reproductive Technology (ART): Cause for Concern or Reassurance? Laxmi A. Kondapalli, Colorado Center for Reproductive Medicine 4:25 PM–5:05 PM S13 States Monitoring Assisted Reproductive Technology (SMART) Collaborative: Promoting State-Based Surveillance of ART and Infertility Sheree Boulet, Centers for Disease Control and Prevention 5:05 PM–5:30 PM Discussion



Break—Fontaine B

Birth Defects Research (Part A) 103:311–347 (2015)

336

TERATOLOGY SOCIETY PROGRAM

MONDAY/TUESDAY



1:30 PM–5:30 PM REACTIVE OXYGEN SPECIES, OXIDATIVE STRESS, AND REDOX SIGNALING IN DEVELOPMENTAL TOXICOLOGY SYMPOSIUM—Mont Royal Chairpersons: Jason M. Hansen, Brigham Young University and Louise M. Winn, Queen’s University



3:30 PM–3:45 PM



3:45 PM–4:25 PM S17 Reactive Oxygen Species (ROS) Formation and Oxidative DNA Damage and Repair in Teratogenesis Peter G. Wells, University of Toronto 4:25 PM–5:05 PM S18 Dysregulation of the Redox Proteome in Teratogenesis: Mediation through Nrf2 Activation Jason M. Hansen, Brigham Young University 5:05 PM–5:30 PM Discussion





1:30 PM–2:10 PM S14 Oxidative Stress and Redox Signaling in Toxicology Barbara F. Hales, McGill University 2:10 PM–2:50 PM S15 Developmental Toxicants That Alter Conceptual Redox States Produce Differential Effects on the Thiol Proteome Craig Harris, University of Michigan 2:50 PM–3:30 PM S16 Reactive Oxygen Species, Embryonic Cell Signaling Pathways, and Teratogenesis Louise M. Winn, Queen’s University Break—Fontaine B

5:30 PM–7:30 PM POSTER SESSION 1 AND EXHIBITS ATTENDED (Joint with INA, NBTS, and OTIS)—Fontaine B Teratology Society Posters: P1–P29 INA, NBTS and OTIS Posters



7:30 PM–10:00 PM TERATOLOGY SOCIETY AND MARTA STUDENT CAREER EVENT—Salon Le Castillon

(Open to Teratology Society, NBTS, INA, and OTIS Students and Postdoctoral Fellows)

TUESDAY, JUNE 30, 2015



7:00 AM–6:00 PM REGISTRATION OPEN—Registration Desk



7:00 AM–6:00 PM SPEAKER READY ROOM OPEN—St. Lambert



6:30 AM–7:00 AM SUNRISE MINI COURSE COFFEE AND CONTINENTAL BREAKFAST—Mont Royal



7:00 AM–8:30 AM SUNRISE MINI COURSE (Separate Registration Required)—Mont Royal Life in the Genetic Fast Lane: Gene Manipulation and Genome Editing to Understand Congenital Diseases Organized by the Education Committee, Chairperson, Janet Hardy, ECC Population Health





7:00 AM–7:45 AM



7:45 AM–8:30 AM

New Techniques in Gene Manipulation and Genome Editing in Vertebrate and Invertebrate Animal Models Yojiro Yamanaka, McGill University Genetically Modified Models to Understand Congenital Diseases: To Boldly Go Faster and Further than Anyone Has Gone Before Richard H. Finnell, The University of Texas at Austin

8:30 AM–9:00 AM ROBERT L. BRENT LECTURE (Joint with OTIS)—Westmount Genetic Mutations Cause Many Birth Defects: What We Learned from the FORGE Canada Project Chairperson: Tacey E.K. White, Exponent, Inc.

Lecturer: Jan M. Friedman, University of British Columbia

Birth Defects Research (Part A) 103:311–347 (2015)

TERATOLOGY SOCIETY PROGRAM

337

TUESDAY



9:00 AM–12:30 PM PUBLIC AFFAIRS SYMPOSIUM (Joint with INA, NBTS, and OTIS)—Westmount Microbiomes: An Underappreciated Organ for Teratologists

Chairpersons: Lori L. Driscoll, Colorado College and Carl L. Keen, University of California, Davis

Introduction

9:05 AM–9:45 AM S19 Measuring the Impact of Diet and Environment on Infant Metabolism and the Microbiome Carolyn M. Slupsky, University of California, Davis 9:45 AM–10:25 AM S20 Impact of Intrapartum Antibiotic Prophylaxis and Other Perinatal Interventions on the Infant Gut Microbiome Anita L. Kozyrskyj, University of Alberta



10:25 AM–10:40 AM



10:40 AM–11:20 AM S21 Maternal Stress and the Neonate Gut Microbiome: Effects on Early Life Programming and Neurodevelopment Eldin Jasarevic, University of Pennsylvania 11:20 AM–12:20 PM S22 Elsevier Distinguished Lecturer Microbiota-Gut-Brain Axis: From Neurodevelopment to Behavior John F. Cryan, University College Cork 12:20 PM–12:30 PM Discussion: What Does the Future Hold?





9:00 AM–9:05 AM

Break—Fontaine B

9:00 AM–12:30 PM PLATFORM SESSION 3—Mont Royal Developmental Toxicity of Pharmaceutical Products

Chairpersons: Jan M. Friedman, University of British Columbia and Kary E. Thompson, Bristol-Myers Squibb Presenting author is underlined.

9:00 AM–9:15 AM

Introduction



9:15 AM–9:30 AM

21



9:30 AM–9:45 AM

22



9:45 AM–10:00 AM

23



10:00 AM–10:15 AM

24

First Trimester Exposure to Citalopram and the Risk of Major Congenital Malformations in a Cohort of Depressed Women Zhao JPZ1,2, Sheehy OS1, Iessa NI1,2, Bérard AB1,2. 1CHU Ste-Justine Hospital, Montréal, QC, Canada, 2University of Montréal, Montréal, QC, Canada. Venlafaxine, a Serotonin-Norepinephrine Reuptake Inhibitor, Induces Fetal Heart Defects in the Rat Huang C1, Ernest SR1, Laurent L2, Bérard A3, Vaillancourt C2, Hales BF1. 1 McGill University, Montréal, QC, Canada, 2INRS-Institut ArmandFrappier and Centre de Recherche BioMed, Montréal, QC, Canada, 3 Sainte-Justine Hospital, Montréal, QC, Canada. Maternal Treatment with Venlafaxine, a Serotonin-Norepinephrine Reuptake Inhibitor, Alters Placental and Fetal Heart Serotonin Systems in the Rat Laurent L1, Huang C2, Ernest SR2, Hales BF2, Vaillancourt C1. 1INRSInstitut Armand-Frappier and Centre de Recherche BioMed, Laval, QC, Canada, 2Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada. Congenital Anomalies in Children of Mothers with Antiepileptic Drugs According to Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study Ban L1, Fleming KM1, Doyle P2, Smeeth L2, Hubbard RB1, Fiaschi L1, Tata LJ1. 1University of Nottingham, Nottingham, United Kingdom, 2London School of Hygiene & Tropical Medicine, London, United Kingdom.

Birth Defects Research (Part A) 103:311–347 (2015)

338

TERATOLOGY SOCIETY PROGRAM

TUESDAY





10:15 AM–10:30 AM

25



10:30 AM–10:45 AM

Break—Fontaine B



10:45 AM–11:00 AM

26



11:00 AM–11:15 AM

27



11:15 AM–11:30 AM

28



11:30 AM–11:45 AM

29



11:45 AM–12:00 Noon

30



12:00 Noon–12:15 PM

31



12:15 Noon–12:30PM

32

Pregnancy Outcome in Women Treated with Etanercept: An Update on the OTIS Autoimmune Diseases in Pregnancy Project Chambers CD, Johnson DL, Luo Y, Jones KL. University of California, San Diego, La Jolla, CA, United States. A Study for Effects of Onartuzumab on Embryo-Fetal and Pre- and Postnatal Development When Administered Intravenously Once Weekly for up to 23 Weeks to Pregnant Cynomolgus Monkeys (Enhanced Design) Halpern W1, Prell R1, Chihaya Y2, Arima A2, Nijem I1, Tarrant J1, O’Mahoney J1, Kaur S1. 1Genentech, South San Francisco CA, United States, 2SNBL Ltd, Kagoshima, Japan. HAART Use during Pregnancy and the Risk of Major Congenital Malformations Bérard AB1,2, Sheehy OS1, Bernatsky SB3, Boucher MB1. 1CHU Ste-Justine, Montréal, QC, Canada, 2University of Montréal, Montréal, QC, Canada, 3 McGill University, Montréal, QC, Canada. Early Vaginal Opening in Female Rats Given Braf-Inhibitor Dabrafenib Is Not Associated with Early Physiological Sexual Maturation Posobiec LM, Vidal J, Laffan S, Hart T, Hughes-Earle A. GlaxoSmithKline, King of Prussia, PA, United States. A Comparison of Rat and Rabbit Developmental Toxicity Study Outcomes of More Than 400 Pharmaceutical Compounds Piersma AH1,8, Theunissen PT2, Beken S4, Cappon GD3, Chen C5, Harrouk W9, Hoberman AM6, van der Laan JW2, Stewart J7. 1RIVM, Bilthoven, Netherlands, 2CBG-MEB, Utrecht, Netherlands, 3Pfizer, Groton, CT, United States, 4FAMHP, Brussels, Belgium, 5ILSI-HESI, Washington, DC, United States, 6Charles River Labs, Horsham, PA, United States, 7 AstaZeneca, Macclesfield, United Kingdom, 8IRAS, Utrecht, Netherlands, 9 US Food and Drug Administration, Washington, DC, United States. US Food and Drug Administration Systematic Review of Pregnancy Registries: Follow-Up Analysis Sahin L1, Hammad H2, Bird S2, Gelperin K2, Hampp C2, Leishear K2, Taylor L2. 1US Food and Drug Administration, Center for Drug Evaluation and Research, Office of New Drugs, Division of Pediatric and Maternal Health, Silver Spring, MD, United States, 2US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, Division of Epidemiology I, Silver Spring, MD, United States. Classification of “Mild” Heart Defects: Challenge for Pregnancy Registries Holmes LB1, Meedzan B1, Beroukhim R2. 1North American AED Pregnancy Registry, MassGeneral Hospital for Children, Boston, MA, United States, 2Pediatric Cardiology, MassGeneral Hospital for Children, Boston, MA, United States.

12:30 PM–1:30 PM LUNCH ON YOUR OWN

Birth Defects Research (Part A) 103:311–347 (2015)

Preconception Treatment with Antiepileptic Drugs and the Occurrence of Fetal Chromosomal Abnormalities: Insights from the North American AED Pregnancy Registry Cramoy CC1, Liu Z1, Quirk MN2, Holmes LB2. 1University of Massachusetts Amherst, Dept. of Nutrition, Amherst, MA, United States, 2 North American AED Pregnancy Registry, Massachusetts General Hospital for Children, Boston, MA, United States.

TERATOLOGY SOCIETY PROGRAM

339

TUESDAY



12:30 PM–1:30 PM MEMBERSHIP COMMITTEE MEETING—Fontaine H



12:30 PM–1:30 PM PUBLIC AFFAIRS COMMITTEE MEETING—St. Pierre



12:30 PM–1:30 PM WEB SITE COMMITTEE MEETING—Fundy



1:30 PM–3:30 PM ILSI HESI WORKSHOP—Westmount Contraception in Clinical Trials: From Animal Data to the Patient

Chairperson: Jane Stewart, AstraZeneca Pharmaceuticals and Belen Tornesi, AbbVie Inc.

1:30 PM–1:35 PM

Introduction Jane Stewart, AstraZeneca Pharmaceuticals 1:35 PM–2:05 PM W8 How Do We Use Animal Data to Determine Contraception for Subjects in Clinical Trials? Susan Kindig, Eli Lilly and Company 2:05 PM–2:35 PM W9 Guidelines for Contraception in Clinical Trials: How Are These Guidelines Used by the Pharmaceutical Companies? Monali Desai, AbbVie Inc. 2:35 PM–3:05 PM W10 Assessment of Drug Interaction Potential of Novel Medicines with Hormonal Contraceptives Glen Carlson, AstraZeneca 3:05 PM–3:30 PM Deliberate and Unintentional Pregnancy Exposure in Clinical Trials: What Can We Learn? Monali Desai and Belen Tornesi AbbVie Inc.



3:30 PM–3:45 PM BREAK—Fontaine B



3:45 PM–6:00 PM GENETIC AND ENVIRONMENT INTERACTIONS OF COMMON MALFORMATIONS SYMPOSIUM—Westmount Chairpersons: Suzan L. Carmichael, Stanford University and John M. Graham, Cedars-Sinai





3:45 PM–3:55 PM



3:55 PM–4:20 PM S23



4:20 PM–4:45 PM S24



4:45 PM–5:10 PM S25



5:10 PM–5:35 PM S26



5:35 PM–6:00 PM

Introduction John M. Graham, Cedars-Sinai Clubfoot Carlos A. Bacino, Texas Children’s Hospital Congenital Heart Defects Seema R. Lalani, Baylor College of Medicine Infantile Hydrocephalus As a Complex Interplay between Genetic and Environmental Risk Factors Hannah Tully, Seattle Children’s Hospital Genetics and Gene-Environment Interaction from the Epidemiologic Perspective Suzan L. Carmichael, Stanford University Discussion

4:00 PM–6:00 PM THE PREGNANCY AND LACTATION LABELING RULE SYMPOSIUM (Joint with OTIS) —Verdun It’s Here, Now What?

Chairpersons: Christina D. Chambers, University of California, San Diego and Melissa S. Tassinari, US Food and Drug Administration

4:00 PM–4:05 PM

Introduction Melissa S. Tassinari, US Food and Drug Administration 4:05 PM–4:20 PM S27 Overview of the Pregnancy and Lactation Labeling Rule Leyla Sahin, US Food and Drug Administration 4:20 PM–4:35 PM S28 Integrating Animal and Pharmacology Data in the New Label Susan B. Laffan, GlaxoSmithKline

Birth Defects Research (Part A) 103:311–347 (2015)

340

TERATOLOGY SOCIETY PROGRAM

TUESDAY/WEDNESDAY





4:35 PM–4:50 PM S29 Clinical Data in the Label: Evaluating Sources and Reliability of Clinical Data Christina D. Chambers, University of California, San Diego 4:50 PM–5:05 PM S30 Considerations for Populating the Lactation Section, 8.2 Jason Sauberan, Rady Children’s Hospital, San Diego 5:05 PM–5:25 PM S31 Translating the New Labels to the Patient: A Clinician’s Perspective Megan E. B. Clowse, Duke University 5:25 PM–6:00 PM Panel Discussion Christina D. Chambers, University of California, San Diego; Megan E.B. Clowse, Duke University; Beth Conover, OTIS Counselor; J. Edward Fisher Jr., US Food and Drug Administration; Susan B. Laffan, GlaxoSmithKline; Leyla Sahin, US Food and Drug Administration; Jason Sauberan, Rady Children’s Hospital, San Diego; Melissa S. Tassinari, US Food and Drug Administration; Tacey E. K. White, Exponent, Inc.

6:00 PM–8:00 PM POSTER SESSION 2 AND EXHIBITS ATTENDED—Fontaine B

Teratology Society Posters: P30–P74

8:00 PM–9:30 PM EDUCATION COMMITTEE MEETING—Fundy WEDNESDAY, JULY 1, 2015



6:30 AM–7:30 AM TERATOLOGY SOCIETY 34TH ANNUAL VOLLEYBALL GAME—Parc Jeanne-Mance



8:00 AM–2:00 PM REGISTRATION OPEN—Registration Desk



8:00 AM–2:00 PM SPEAKER READY ROOM OPEN—St. Lambert



8:30 AM–9:30 AM TERATOLOGY SOCIETY AND EUROPEAN TERATOLOGY SOCIETY EXCHANGE LECTURE—Westmount Endocrine Disruptors: A Regulatory Solution in Search of a Problem? Chairpersons: Manon Beekhuijzen, WIL Research Europe BV and Susan L. Makris, US Environmental Protection Agency

Teratology Society (L2) Endocrine Disruptors: Are They Causing Adverse Effects in Humans? Elaine Z. Francis, Sandcastle Toxicology Associates

European Teratology Society (L3) Endocrine Disruptors: Are Regulations the Solution? Nina Hallmark, Bayer SAS



9:30 AM–12:30 PM CEREBRAL PALSY: HISTORY, MECHANISMS AND PREVENTION SYMPOSIUM—Westmount Chairpersons: Nigel Paneth, University of Michigan and L. David Wise (ret.)

9:30 AM–9:45 AM

Introduction

9:45 AM–10:15 AM S32 Birth Defects and Cerebral Palsy Karin B. Nelson, National Institute of Neurological Disorders and Stroke (ret.) 10:15 AM–10:45 AM S33 The Causation and Prevention of Cerebral Palsy Nigel Paneth, University of Michigan 10:45 AM–11:15 AM Warkany Tea—Montréal Ballroom Foyer 11:15 AM–11:45 AM S34 Clinical Diagnosis and Management of Cerebral Palsy Peter Rosenbaum, McMasters University

Birth Defects Research (Part A) 103:311–347 (2015)

TERATOLOGY SOCIETY PROGRAM

341

WEDNESDAY





11:45 AM–12:15 PM S35 Neuroprotection and Treatment of Cerebral Palsy Michael V. Johnston, Kennedy Krieger Institute 12:15 PM–12:30 PM Discussion

9:30 AM–12:30 PM PLATFORM SESSION 4—Mont Royal Alternative Models

Chairpersons: Wafa A. Harrouk, US Food and Drug Administration and Nicole C. Kleinstreuer, ILS/NICEATM Presenting author is underlined.

9:30 AM–9:45 AM

Introduction



9:45 AM–10:00 AM

33

Evaluation of 1066 ToxCast Chemicals in a Human Stem Cell Assay for Developmental Toxicity Knudsen TB1, Judson RS1, Baker NC1,2, Leung MCK1. 1US Environmental Protection Agency, NCCT, Research Triangle Park, NC, United States, 2 Lockheed-Martin, Research Triangle Park, NC, United States. Compound Ranking Using a Biomarker-Based Human Pluripotent Stem Cell In Vitro Assay for Developmental Toxicity: Chemotype Coverage and Case Studies Palmer JA, Egnash LA, Smith AM, Burrier RE, Donley ELR, Kirchner FR. Stemina Biomarker Discovery, Inc., Madison, WI, United States. Comprehensive Maternal Serum Proteomics for Biomarkers Discovery in Noninvasive Prenatal Diagnosis of Congenital Heart Defects Yuan Z, Chen L, Gu H, Li J, Wei X. Shengjing Hospital, China Medical University, Shenyang, China. Vascular Developmental Toxicity of TNP-470 and 5HPP-33 Assessed with ToxCastDB and Anchored to Functional Assays for Angiogenesis and Embryogenesis Knudsen TB1, Franzosa JA1, Baker NC1,2, Spencer RS2, Hunter ES1, Kleinstreuer NC3, Ellis-Hutchings R4, Carney EW4. 1US Environmental Protection Agency, Research Triangle Park, NC, United States, 2LockheedMartin, Research Triangle Park, NC, United States, 3ILS/NICEATM, Research Triangle Park, NC, United States, 4The Dow Chemical Company, Midland, MI, United States.



10:00 AM–10:15 AM

34



10:15 AM–10:30 AM

35



10:30 AM–10:45 AM

36



10:45 AM–11:15 AM

Warkany Tea—Montréal Ballroom Foyer



11:15 AM–11:30 AM

37



11:30 AM–11:45 AM

38



11:45 AM–12:00 Noon

39

Prenatal Alcohol Exposure and Cardiac Neural Crest Ablation Both Result in Similar Defects in Cardiac Function and Structure Karunamuni G, Ma P, Peterson LM, Gu S, Doughman YQ, Jenkins MW, Rollins AM, Watanabe M. Case Western Reserve University, Cleveland, OH, United States. A 3-D In Vitro Mini-Brain Model to Study Parkinson’s Disease Pamies D1, Wiersma DMM1, Block K1, Pardo CA2, Barreras P2, Kyro K3, Leist M4, Hartung T1, Hogberg H1. 1Center for Alternatives to Animal Testing, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States, 2Department of Neurology, Division of Neuroimmunology and Neuroinfectious Disorders, Johns Hopkins University, Baltimore, MD, United States, 3US Army Edgewood Chemical Biological Center, Aberdeen Proving Grounds, Aberdeen, MD, United States, 4Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Universitätsstr, Konstanz, Germany. Using ToxCast/Tox21 HTS Assays to Assess Endocrine Disruption Kleinstreuer NC1, Allen D1, Casey WM2. 1ILS/NICEATM, Research Triangle Park, NC, United States, 2NIH/NIEHS/DNTP/NICEATM, Research Triangle Park, NC, United States.

Birth Defects Research (Part A) 103:311–347 (2015)

342

TERATOLOGY SOCIETY PROGRAM

WEDNESDAY



12:00 Noon–12:15 PM

40



12:15 PM–12:30 PM

41

Triphenyl Phosphate and Isopropylated Triphenyl Phosphates Induce Differentiation of Murine Embryonic 3T3-L1 and Human Preadipocytes to Mature Adipocytes Tung EWY, Boucher JG, Ahmed S, Atlas E. Health Canada, Ottawa, ON, Canada. An Evaluation of Daphnia pulex As a Model Organism for Evaluating Multi-Stressor Interactions across the Lifespan Gohlke JM1, Doke D2, Hudson SL1, Dawson JA1, Shwartz TS1, Roberts JE1. 1 University of Alabama at Birmingham, Birmingham, AL, United States, 2 University for Development Studies, WA, Ghana.



12:30 PM–1:00 PM CELEBRATING ED CARNEY: SCIENTIST, FRIEND, AND MUSICIAN—Westmount



12:30 PM–1:30 PM LUNCH ON YOUR OWN



1:30 PM–4:30 PM MECHANISMS OF POSTNATAL REPRODUCTIVE DEVELOPMENT/PUBERTY AND METHODS FOR EVALUATION WORKSHOP—Westmount Chairpersons: Susan B. Laffan, GlaxoSmithKline and Kary E. Thompson, Bristol-Myers Squibb

1:30 PM–1:45 PM



1:45 PM–2:15 PM W11 Improving the Assessment of Endocrine Disrupting Chemicals (EDC) Effects on Puberty Tammy E. Stoker, US Environmental Protection Agency 2:15 PM–2:45 PM W12 In Vivo Assessments of Puberty with Focus on Female Rodent Model Susan B. Laffan, GlaxoSmithKline



2:45 PM–3:00 PM



3:00 PM–3:30 PM W13 Assessing the Effect of Long-Acting GLP-1 Agonists on Onset of Puberty in Rats Kary E. Thompson, Bristol-Myers Squibb 3:30 PM–4:00 PM W14 Clinical Perspectives on Environmental Influences on Pubertal Timing Mary M. Lee, University of Massachusetts Memorial Children’s Medical Center 4:00 PM–4:30 PM Discussion







Introduction

Break—Montréal Ballroom Foyer

1:30 PM–4:30 PM PLATFORM SESSION 5—Mont Royal

Mechanisms of Teratogenesis

Chairpersons: Michelle Carll Helms, Thomas Jefferson University and Sonja A. Rasmussen, Centers for Disease Control and Prevention Presenting author is underlined.

1:30 PM–1:45 PM

Introduction



1:45 PM–2:00 PM

42



2:00 PM–2:15 PM

43

Genetic Differences in Pup Survival, Biochemistry, and Gene Expression following Developmental Exposure to Polychlorinated Biphenyls Curran CP, Klinefelter K, Brown J, Bates CT, Kromme M, Hays B, Weimer J, Hampton S. Northern Kentucky University, Highland Heights, KY, United States. Expression Profiles of a Subset of Placental Imprinted Genes May Predict Infant Neurobehavioral Outcomes Green BB1, Kappil M2, Lambertini L2, Armstrong DA1, Geurin DG1, Lester BM3, Chen J2, Marsit CJ1. 1Geisel School of Medicine at Dartmouth College, Hanover, NH, United States, 2Icahn School of Medicine at Mount Sinai, New York, NY, United States, 3Alpert Medical School of Brown University and Women and Infants Hospital, Providence, RI, United States.

Birth Defects Research (Part A) 103:311–347 (2015)

TERATOLOGY SOCIETY PROGRAM

343

WEDNESDAY



2:15 PM–2:30 PM

44

Disruption in Placental Expression of Imprinted Genes Is Associated with Birthweight Kappil M1, Lambertini L1, Guerin D2, Green B2, Marsit C2, Chen J1. 1Icahn School of Medicine at Mount Sinai, New York, NY, United States, 2Geisel School of Medicine at Dartmouth, Hanover, NH, United States. Epigenetic Modifications of Histone H3 in Brains and Livers of Fetal DNA Repair-Deficient Oxoguanine Glycosylase 1 (ogg1) Knockout Mice Exposed In Utero to Ethanol Bhatia S1, Wells PG1,2. 1Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada, 2Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.



2:30 PM–2:45 PM

45



2:45 PM–3:00 PM

Break—Montréal Ballroom Foyer



3:00 PM–3:15 PM

46



3:15 PM–3:30 PM

47



3:30 PM–3:45 PM

48



3:45 PM–4:00 PM

49



4:00 PM–4:15 PM

50

Heritable Germline Chromatin Desilencing Mediated by the Environmental Alteration of the Epigenome Camacho J, Kreik S, Allard P. University of California, Los Angeles, Los Angeles, CA, United States. Copper Influences on Markers of Motility in Endothelial Cells: Potential Role in the Development of the Vascular System in Embryos Lanoue L, Demyan L, Keen CL. University of California, Davis, CA, United States. The Role of JNK Activation in Cell Survival after Cadmium Exposure in Micromass Culture of Mouse Embryo Limb Bud Cells Kapron CM, Alhoesh A. Trent University, Peterborough, ON, Canada. The Role of Previous Miscarriages and Single Nucleotide Polymorphisms in Developmental Genes in the Etiology of Anorectal Malformations van der Putte R1, Wijers CHW1, de Blaauw I2,3, Marcelis CLM4, Sloots CEJ3, Brooks A5, Broens PMA6, Brunner HG4, van der Zanden LFM1, van Rooij IALM1, Roeleveld N1,7. 1Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands, 2Department of Surgery-Pediatric Surgery, Radboudumc Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands, 3Department of Pediatric Surgery, Sophia’s Children’s Hospital, Erasmus Medical Centre, Rotterdam, Netherlands, 4Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands, 5Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, Netherlands, 6Department of Surgery, Division of Pediatric Surgery, University Medical Centre Groningen, Groningen, Netherlands, 7 Department of Pedatrics, Radboudumc Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands. Copy-Number Variant Analysis of Classic Heterotaxy Highlights the Importance of Body Patterning Pathways Hagen EM1, Sicko R2, Kay DE2, Rigler S3, Dimopoulos A1, Warmerdam B4, Ahmad S4, Doleman M4, Fan R1, Romitti P5, Browne M2, Caggana M2, Brody L6, Shaw G7, Jelliffe-Pawlowski L8,9, Mills JL1. 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, United States, 2New York State Department of Health, Albany, NY, United States, 3Naval Medical Center, Portsmouth, VA, United States, 4California CBDMP, Sacramento, CA, United States, 5 Universtiy of Iowa, Iowa City, IA, United States, 6National Human Genome Research Institute, Bethesda, MD, United States, 7Stanford University, Stanford, CA, United States, 8California Genetic Disease Screening Program, Sacramento, CA, United States, 9Univesity of California, San Francisco, San Francisco, CA, United States.

Birth Defects Research (Part A) 103:311–347 (2015)

344

TERATOLOGY SOCIETY PROGRAM

WEDNESDAY/THURSDAY



4:15 PM–4:30 PM

51

Copy Number Variants in a Population-Based Investigation of Klippel Trenaunay Weber Syndrome Dimopoulos A1, Sicko R2, Kay DE2, Rigler S3, Fan R1, Romitti P4, Browne M2, Druschel C2, Caggana M2, Brody L5, Mills JL1. 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, United States, 2New York State Department of Health, Albany, NY, United States, 3Naval Medical Center Porthsmouth, Porthsmouth, VA, United States, 4University of Iowa, Iowa City, IA, United States, 5National Human Genome Research Institute, Bethesda, MD, United States.



4:45 PM–6:15 PM BUSINESS MEETING—Westmount



6:30 PM–7:30 PM BANQUET RECEPTION—Montréal Ballroom Foyer



7:30 PM–11:00 PM BANQUET—Outremont Travel Awards James C. Bradford Memorial Student Poster Awards Wilson Presentation Awards Marie Taubeneck Award Birth Defects Research Distinguished Scholar Awards Edward W. Carney Distinguished Service Award Recognition of Other Awards Presented Throughout the Week THURSDAY, JULY 2, 2015



7:00 AM–10:00 AM COUNCIL 2 MEETING—Fundy

Birth Defects Research (Part A) 103:311–347 (2015)

TERATOLOGY SOCIETY PROGRAM

345

Online Membership Application Why you should join… • To grow your professional network! Our online Career Center links job candidates with employers and positions in developmental and reproductive toxicology as well as related biological sciences. Involvement in committees and our annual meetings provides numerous formal and informal networking opportunities. • To showcase your expertise! You can have the opportunity to engage in leadership and public-facing communication activities that highlight your expertise. • To stay informed! Regular and Associate membership includes an electronic subscription to the journal, Birth Defects Research. Students may subscribe to the journal at a reduced rate. Members also have access to our robust members-only website and social media platform, BDR Connection, which includes blogs, educational resources, weekly email digests and more. • To share ideas that make an impact! By working together in a multidisciplinary way, our world-renowned experts are dedicated to advancing science in order to eliminate or ameliorate birth defects. Our members specialize in teratology, cell and molecular biology, developmental biology, reproductive toxicology, endocrinology, nutritional biochemistry, genetics, and epidemiology, as well as the clinical disciplines of prenatal medicine, pediatrics, obstetrics, neonatology, medical genetics, and teratogen risk counseling. Join today and save! Payment of the nonmember registration fee for the 55th Annual Meeting includes first-year membership dues if a Regular or Associate membership application is also received by July 1st. Online membership application can be completed via the Teratology Society website in a matter of minutes. Apply for membership via the Teratology Society website today.

www.teratology.org Birth Defects Research (Part A) 103:311–347 (2015)

346

TERATOLOGY SOCIETY PROGRAM

Exhibitor Information (as of March 27, 2015)

Exhibits and Posters are located in the Fontaine B. Although the Exhibit Hall will be open Sunday afternoon through Tuesday evening, the exhibits will be attended only during the times listed below. Exhibits Attended   Sunday, June 28   6:00 PM–7:00 PM

Monday, June 29 5:30 PM–7:30 PM

Tuesday, June 30 6:00 PM–8:00 PM

All information printed in this exhibitor section is listed in alphabetical order and was submitted by the exhibiting company.

CHARLES RIVER 251 Ballardvale Street Wilmington, MA 01887 United States

    Tel: 877.CRIVER.1     Fax: 978.988.9236

Email: [email protected] Website: www.criver.com

Charles River provides a comprehensive service in developmental, reproductive, and juvenile toxicology for the progression of your compound. Studies are performed in multiple species using various routes of dose administration. Our range of capabilities, combined with leading scientific expertise and over 25 years of historical data, results in timely nonclinical reproductive toxicology programs with regulatory acceptance.

EXPERIMUR 4045 S. Morgan Street Chicago, IL 60609 United States

    Tel: 773.254.2700     Fax: 773.254.2723

Email: [email protected] Website: www.experimur.com

Experimur is a full-service toxicology testing and research laboratory with extensive experience in the conduct of developmental (Seg I, II, & III) and reproductive (single and multi-generation) toxicity assessments, including sperm morphology and vaginal cytology, as well as general toxicity (acute, subchronic, chronic, and carcinogenicity), neurotoxicity, and pharmacokinetic/ADME studies in species ranging from rodents to primates. With an experienced and well-trained team that has worked together for over 28 years and successfully completed thousands of GLP-compliant preclinical studies, we are committed to providing our customers with top quality and unmatched service. We invite you to visit our spectacular custom-built, AAALAC-accredited, USDA-registered, 54,000 sq ft state-of-the art facility and vivarium, which includes extensive in-house support services for histology diagnostic pathology, clinical pathology, and analytical chemistry.

Birth Defects Research (Part A) 103:311–347 (2015)

TERATOLOGY SOCIETY PROGRAM

347

EXPONENT, INC. 1800 Diagonal Road, Suite 500 Alexandria, VA 22314 United States

    Contact: Dr. John DeSesso     Tel: 571.227.7261

Email: [email protected] Website: www.exponent.com

Exponent’s veteran toxicologists and epidemiologists are drawn from the chemical and pharmaceutical industries, academia, and government. They have international regulatory experience in designing and interpreting developmental and reproductive toxicity (DART) and developmental neurotoxicology studies; assessing potential endocrine disruption; performing quantitative risk assessments and cancer risk assessments related to children. Our experts are also ready to assist you in complying with the new US FDA Pregnancy and Lactation Labeling Rule. EXPONENT, INC.BOOTH 10

SAN DIEGO INSTRUMENTS 9155 Brown Deer Road, Suite 8 San Diego, CA 92121 United States

    Contact: Bob Lischer     Tel: 858.530.2600

Email: [email protected] Website: www.sandiegoinstruments.com

San Diego Instruments (SDI) has served the scientific community for over 30 years as a comprehensive resource for the design, manufacture and distribution of scientific testing systems used in human and animal behavioral studies. Utilized in laboratories and cited in research papers worldwide, SDI systems represent the industry benchmark for quality and longevity.

THE TERATOLOGY SOCIETY 1821 Michael Faraday Drive, Suite 300 Reston, VA 20190 United States

    Tel: 703.438.3104     

Email: [email protected] Website: www.teratology.org

The Teratology Society is composed of a multidisciplinary group of scientists including researchers, clinicians, epidemiologists, and public health professionals from academia, government, and industry who study birth defects, reproduction, and disorders of developmental origin. Our Mission is to prevent birth defects and disorders of developmental origin by: promoting research and exchange of ideas, communicating information to health professionals and other interested parties, and providing education and training. Visit the booth to learn more about the Society and membership.

US FOOD AND DRUG ADMINISTRATION OFFICE OF WOMEN’S HEALTH RESEARCH 10903 New Hampshire Avenue Building 32 Room 2333 Silver Spring, MD 20993 United States

    Tel: 301.796.9440

Website: www.fda.gov/womens

The US Food and Drug Administration Office of Women’s Health addresses the health issues of the nation’s women by funding scientific research and collaborating with national organizations and government agencies to sponsor outreach and education efforts.

Birth Defects Research (Part A) 103:311–347 (2015)

Birth Defects Research (Part A) 103:348–350 (2015)

TERATOLOGY SOCIETY LECTURE ABSTRACTS

(Presenter designated by underlined author.)

Birth Defects Research (Part A) Clinical and Molecular Teratology 103:348–350 (2015)

LECTURE ABSTRACTS

Patricia Rodier Mid-Career Award in Research and Mentoring (Joint with NBTS) Chairpersons: Bruce K. Beyer, Sanofi US Inc. and Lori L. Driscoll, Colorado College

L1

STANWOOD GD. Florida State University, College of Medicine, Tallahassee, FL, United States. Developmental Causes and Consequences of Drug Abuse Brain formation and function relies on the complex interplay of a variety of genetic and environmental factors through protracted periods of gestational and postnatal development. Abnormalities in neurodevelopmental programming contribute to developmental delays and multiple neurological and psychiatric disorders, often with symptom onset much later than the actual induction of pathology. This talk will review several genetic and pharmacological models of monoamine modulation during pre- and postnatal development, each of which produces long-lasting changes in brain function and behavioral responsiveness. Clinical studies and significance will be integrated with mechanistic preclinical studies to define our current knowledge base and identify gaps for future investigation.

349

Teratology Society and European Teratology Society Exchange Lecture Chairpersons: Manon Beekhuijzen, WIL Research Europe BV and Susan L. Makris, US Environmental Protection Agency

L2

FRANCIS EZ. Sandcastle Toxicology Associates, Ventnor, NJ, United States. Endocrine Disruptors: Are They Causing Adverse Effects in Humans? The surge in concern about endocrine disruptors (EDs) began in the early 1990s, following an increased number of reports of adverse effects in wildlife following environmental exposure. Results from studies in laboratory animal models confirmed these findings and raised additional concerns about the breadth of endocrine systems that may be affected. These observations led to concerns about the potential of EDs to cause adverse effects in humans, since the endocrine system is fairly well conserved across species. At that time, it was well recognized that there were adverse effects in the reproductive tracts of offspring of women who had taken DES during pregnancy and cognitive deficits in offspring of women who had higher levels of PCBs. So, the question raised was, are there other chemicals and other targets, in particular following exposures at environmentally relevant levels, for which there should be concern in humans? Over a thousand human studies on EDs have been conducted over the last 20+ years to address this issue. There are increasing numbers of reports in the epidemiological and other human studies’ literature showing possible health effects associated with EDs at environmentally relevant levels. However, since most epidemiological studies are by nature observational rather than experimental, a number of possible explanations for an observed association need to be considered before a cause-effect relationship can be inferred. The determination of a cause-effect relationship is based on a careful review and judgment of all relevant information available, and never on the basis of one or two studies alone. Considerations to help assess the evidence of causality were published in 1965 (Bradford-Hill), which are still used. These include consistency of findings, strength of association, specificity of association, temporal relationship, dose-response relationship, biological plausibility, and coherence of evidence. Both toxicologic and epidemiologic studies have different strengths and weaknesses in their application of assessing risks of EDs to humans. So what can we infer from the wealth of findings related to EDs and their potential human health effects? What recommendations can be made to improve the value of human studies in our understanding regarding EDs as a potential public health concern?

Birth Defects Research (Part A) 103:348–350 (2015)

350

LECTURE ABSTRACTS

L3

HALLMARK N. Bayer SAS, Sophia-Antipolis, France. Endocrine Disruptors: Are Regulations the Solution? A key purpose for government regulations is to address public concern. Since the 1990’s several governments have been trying to develop a regulatory solution to the public concern around the potential for xenobiotics to adversely impact human health, in particular the endocrine systems. In the ~20 years since the 1996 multi-stakeholder kick-off meeting in Weybridge, UK, there has been mixed success. Public concerns have grown beyond the original oestrogenicpotential of xenobiotics to include potential impact on androgenic, thyroid and other hormone systems, all relevant to healthy human reproduction and development and therefore our two Societies. Our scientific understanding of human, plant and wildlife endocrine biology has expanded enormously. We now know a lot more about how healthy organisms exhibit dramatic but normal fluctuations in hormone levels—depending on the time of day, season, age, activity, and diet. So, can further regulations improve public health? Is there a health problem? Could it be said that there is nothing unique about ED-mediated health effects and that existing regulations already address the main health endpoints linked to this mode of action e.g. cancer, reproductive and developmental changes. Meantime, a precautionary approach has been applied in certain regulated regions: consider that certain EU chemicals have restricted market access due to ED indications? Consider the US EPA Endocrine Disruptor Screening Program and its published “universe” of 10,000 potential ED chemicals? Consider the efforts of various expert advisory groups e.g. UNEP, OECD, and expert reports e.g. WHO/IPCS 2002 and 2012, etc. What do they say about the need for ED-related regulations? Key questions remain—is there an ED-mediated public health problem vs. concern? If so, is this not already being addressed through existing regulatory frameworks? If not, will the latest regulatory proposals (product restrictions) solve the problem? What is the potential public cost/health benefit of additional regulations? Is further investment of scientific and regulatory resources warranted? Are the regulatory activities developing a solution without a problem to solve? Let’s talk about it.

Birth Defects Research (Part A) 103:348–350 (2015)

SYMPOSIUM ABSTRACTS

TERATOLOGY SOCIETY

351

SYMPOSIUM ABSTRACTS

(Presenter designated by underlined author.)

Birth Defects Research (Part A) 103:351–366 (2015)

352

SYMPOSIUM ABSTRACTS

Paternal Exposures Impact Progeny Outcome by Altering the Sperm Genome and Epigenome Symposium Chairpersons: Barbara F. Hales and France-Helene Paradis, McGill University

S1

S2

As the age of paternity increases, there is growing societal concern regarding the potential consequences of this increase to progeny. Several epidemiological studies have established clear links between paternal age and an increased incidence in the next generation of conditions such as autism, cardiovascular anomalies, ADHD, and schizophrenia. Using animal studies, we have found that increasing paternal age affects progeny outcome, sperm quality, and the response to oxidative stress. We found significantly altered expression with age of genes involved in DNA damage/repair, oxidative stress, and cell adhesion in isolated pachytene spermatocytes. Further analysis of these cells demonstrated that genes involved in the base and nucleotide excision repair (BER, NER) pathways were specifically altered during aging. Furthermore, in aged males there was an increase in 8-oxo-2´-deoxyguanosine (8-oxodG) immunoreactivity in the testes and in the number of spermatozoa positive for 8-oxodG; thus, downregulation of the BER pathway leads to oxidative-stress related deficient repair of 8-oxo-dG lesions in germ cells. We also found changes in the expression of over 70 transcripts involved in cell adhesion, and this was associated with a gradual collapse of the bloodtestis barrier between 18 and 24 months. Using a newly developed method to culture pachytene spermatocytes and round spermatids, we found that the cells from aged animals had lower resistance to culture, a higher apoptosis rate, and a decreased ability to withstand challenge by stressors of oxidative stress. The damage to spermatogenic cells from aged rats led us to hypothesize that spermatogonial stem cells may be affected. Using CD9+ enriched GFP-marked spermatogonial cells from young and aged rats and transplanting them into the testes of busulfan-treated nude mice, we found that colony numbers and size as well as gene expression were affected by age. These molecular alterations in the spermatogonial-enriched population of cells from the testes of aged rats imply that stem/progenitor spermatogonia are contributors to the germ cell origin of reproductive aging. These studies lay the molecular foundation for understanding how male germ cells age and how these changes can result in altered progeny outcome. These studies were funded by the Canadian Institutes for Health Research.

There is a renewed interest in identifying environmental agents and lifestyle factors that cause an increase in risk of heritable disease. Several paternal exposures, such as tobacco smoking, pesticides and polycyclic aromatic hydrocarbons, have been epidemiologically associated with abnormal reproductive outcomes. However, risk factors for male-mediated developmental toxicity remain an understudied area. It is also becoming increasingly clear that the landscape of the eukaryotic genome is complex, and that a diversity of genomic changes can be induced in the germ cells and have an impact on the health of the offspring. Therefore, proper characterization of the genotoxic effects of an exposure on germ cells requires assays that assess different mutational mechanisms. Research in our laboratory uses the Muta™Mouse model to develop improved testing methods for analyzing various germ cell mutagenicity endpoints and identifying environmental factors that affect mutation frequencies in germ cells. We have used two well established germ cell mutagens, N-ethyl-Nnitrosourea (ENU) and benzo(a)pyrene (BaP) to demonstrate: the presence of a saturable DNA repair mechanism in spermatogonia that is able to prevent mutations at low doses but not at high doses; that dividing spermatogonia represent a window of peak sensitivity for the induction of mutations during spermatogenesis; and, that analysis of simple tandem repeats by single-molecule PCR is a promising approach for studying the induction of mutations in germ cells of potentially any species. Finally, we have integrated whole genome analyses (i.e., comparative genomic hybridization arrays and next generation sequencing) into our mutational analyses and are currently characterizing copy number variation (CNV) and point mutations in the offspring of males exposed to BaP. These methods are promising tools for understanding the mechanisms of induction of transmissible genetic damage and the consequences of paternal occupational, environmental, or lifestyle exposures on abnormal reproductive outcomes.

ROBAIRE B. Departments of Pharmacology and of Obstetrics and Gynecology, McGill University, Montréal, QC, Canada. Impact of Paternal Aging on Male Germ Cells and Progeny

Birth Defects Research (Part A) 103:351–366 (2015)

MARCHETTI F, O’BRIEN JM, BEAL MA, MEIER M, YAUK CL. Health Canada, Ottawa, ON, Canada. Paternal Lifestyle As a Source of Germline Mutations Transmitted to Offspring

SYMPOSIUM ABSTRACTS

S3

KIMMINS S, LAMBROT R, SIKLENKA K, LAFLEUR C. Departments of Animal Science and Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada. The Role of the Environment and the Sperm Epigenome in Development and Disease Despite the father transmitting half the heritable information to the embryo the focus on preconception health has largely been on the mother. New studies highlight the role of the father in disease transmission via nongenetic inheritance, through epigenetic mechanisms. Epigenetic mechanisms include, DNA methylation, posttranslational modifications of histones and noncoding RNAs. Paternal effects have been linked to developmental abnormalities and complex diseases such as cancer, diabetes and obesity. Studies in humans and animals have linked epigenetic inheritance to the transmission of environmentally-induced phenotypic traits from the father to the developing embryo and these have been associated with altered gene expression and developmental abnormalities in first and second offspring generations The genome in mature spermatozoa is packaged in a very unique manner. Whereas the majority of the genome is packaged by sperm-specific nucleoproteins, the protamines, regulatory regions of many genes retain nucleosomes. Moreover, such nucleosomes carry posttranslational modifications in a manner that is highly suggestive of a function in embryo development. We have shown that paternal folate deficiency (FD) is associated with increased birth defects, minor alterations to DNA methylation in the sperm including at genes implicated in development and chronic disease (Lambrot et al., 2013 Nature Communications). We also showed folate deficiency altered global levels of histone methylation in sperm, suggesting their involvement in epigenetic inheritance. To address the role of modified histones in sperm for embryonic development we generated transgenic mice overexpressing the human histone demethylase LSD1/KDM1A. Offspring sired by such transgenic mice suffered from major developmental abnormalities and increased neonatal death. Remarkably, overexpression of KDM1A in heterozygote fathers affected wild type offspring as well, even for three following generations. Using epigenomic and transcriptomic approaches we have been characterizing the effects of diets and transgene expression on the spermatogonia and sperm epigenome to identify windows in spermatogenesis that are sensitive to reprogramming and to determine the potential for dietary interventions to correct diet-induced epimutations. This research has been funded by CIHR grants to SK.

353

S4

SZYF M, PETROPOULOS S, MATTHEWS SG. Department of Pharmacology and Therapeutics, McGill University, Montréal, QC, Canada. The Transgenerational Effects of Paternal Glucocorticoid Treatment Epidemiological data from humans and animals suggest that parental stressful experiences are transmitted across generations and affect both behavioral and physical phenotypes in their offspring. Parental stressful experience could be transmitted through exposure in utero, through exposure after birth to maternal behavior and through exposure of paternal gametes to stress either in utero or later in life. These experiences could then be transmitted across several generations either through a cycle of behavioral exposures to stress or through “gamete-mediated” transgenerational transmission across three generations at least. But what are the mechanism that embed these experiences in the offspring? It is particularly difficult to understand how preconception exposure of gametes to stress would affect future generations? Our working hypothesis is that changes in DNA methylation embed the experiences in the genome and are involved in transgenerational transmission of these experiences. The critical challenge is identifying a mechanism that translates perception of stress in parents into a physical change in brain wiring in offspring. The stress hormone glucocorticoid that is released in response to stress is hypothesized to play a critical role in translating the behavioral signals into DNA methylation alterations. The Glucocorticoid receptor is a transacting factor that could modify the state of activity and chromatin state of genes is present in sperm and might be mediating the transmission of stress to future generations. We tested therefore whether exposure of healthy adult animals will result in changes in DNA methylation in sperm and whether this exposure has an effect on the offspring? A significant increase in global nonCpG methylation was observed in F0 sperm 60 days following sGC treatment. In the hippocampus and kidney of Postnatal Day 50 (PND50) and PND240 male offspring derived from fathers exposed to sGC, significant differences in mineralocorticoid receptor (Nr3c2; Mr), estrogen alpha receptor (Nr3a1; Ers1), and glucocorticoid receptor (Nr3c1; Gr) expression were observed. These findings provide proof of principle that adult glucocorticoids might be linking the brain that senses behavioral exposure and the gametes resulting in changes in DNA methylation and alter phenotype across generations.

Birth Defects Research (Part A) 103:351–366 (2015)

354

SYMPOSIUM ABSTRACTS

Wiley-Blackwell Symposium Are Human Skeletal Malformations the Result of Embryonic Arterial Dysgenesis? Chairpersons: Lewis B. Holmes, MassGeneral Hospital for Children and David R. Hootnick, SUNY Upstate Medical University

S5

HOOTNICK D, PACKARD D. SUNY Upstate Medical University, Syracuse, NY, United States. Embryonic Arterial Dysgenesis and Long Bone Deficiencies The variety of human congenital limb malformations is perplexing. Current nomenclature is authoritative but lacks etiologic significance. Radiologically visible skeletal dysmorphologies have tended to engage researchers to the relative neglect of the soft tissues, including the arterial tree. Lower extremity skeletal reductions involving the proximal femur, fibula and midline metatarsals have been observed to correspond to the 5th–6th week (postfertilization) regions of embryonic arterial ingrowth, when the arterial and skeletal structures are rapidly undergoing coincidental developmental alteration. Arteriographic evaluation of affected human lower extremities reveals not only reduction and absence of arteries, which correspond to the dystrophic skeletal changes, but also the persistence of atavistic embryonic arteries; the combination of absent and atavistic arteries provides clues not only to the timing but also to the pathomechanics of both the arterial and skeletal malformations. Analysis of dissections of a spectrum of lower extremity skeletal dysmorphologies suggests the embryonic arterial alterations appear initially; other soft tissue alterations appear later. We further infer that the limb malformations have occurred after the completion of specification (patterning) of normal limb models as “postspecification” errors. A majority of human lower limb congenital limb malformations may be most accurately interpreted as the result of postspecification embryonic arterial dysgenesis and its sequelae. The overt physical malformations vary, according to the timing and anatomic position of the arterial transitional error(s). Absent any definitive distinction between naturally occurring human limb dysmorphologies and experimentally produced skeletal reductions, aberrant embryonic angiogenesis appears as a significant precursor to many dystrophic clinical and experimental skeletal reductions.

Birth Defects Research (Part A) 103:351–366 (2015)

S6

DESESSO JM1, FARMER DR2, PACKARD JR DS3. 1Exponent, Inc, Alexandria, VA, United States, 2Monsanto Company, St Louis, MO, United States, 3SUNY Upstate Medical University, Syracuse, NY, United States. Anatomical Inferences Regarding Gestational Stage and Location of Teratogenic Events in Malformed Human Limbs Human extremities develop from early, undifferentiated limb buds to well defined and properly rotated appendages during the 21st to the 56th days of gestation. Limb development is complex. The early limb bud, comprising a mass of somatopleuric mesenchymal cells overlain by an ectodermal jacket, is invaded by neural crest cells, somitic myoblasts, and vasculature as it expands and acquires 3 areas for future development of the long bones, associated musculature and vessels of the limbs: stylopod, zeugopod, and autopod. During this period of development, the tissues of each segment become sequentially committed to form limb tissues (i.e., they have undergone conditional specification), the exact developmental destiny of each cell has not yet been decided. As development of each region of the limb progresses, vascular patterns are formed and remodeled in concert with development of the specific skeletal and muscular elements that are found in the region. Under normal conditions, the ontogeny of the vascular arrangement is predictable both anatomically and temporally. During chemically-induced teratogenesis of limbs in experimental models (e.g., hydroxyurea in rats), bilateral major disruption of limb bud anatomy in one limb segment followed by a period of repair is termed a “specification defect” which includes complete absence of bones and related soft tissues within that segment. Vascular ontogeny is delayed as visualized through sequential intravascular India ink preparations of embryos. A teratogenic event after specification in a segment has occurred (post-specification), causes mis-shapened/ diminished bones with relatively normal soft tissues. In both cases, the vascular patterns at term appear to have been arrested. Careful dissections of idiopathic malformed human lower extremities revealed morphologies consistent with post-specification injury in the proximal leg, but specification injuries distally. While at first glance the presence of different types of malformation in the same limb may appear contradictory, a single teratogenic event could cause both types because specification of segments occurs in a proximodistal sequence. Additionally, the adult arterial configurations often mimic arterial patterns at a particular embryonic stage and can help to provide a basis both to ascertain the gestational stage when the perturbation occurred and to explain the pattern of malformations.

SYMPOSIUM ABSTRACTS

S7

WOLPERT L. University College, London, United Kingdom. Patterning the Limb In order to understand limb abnormalities it is necessary to understand normal development. Our studies have shown that the positional information plays a key role in limb development. A gradient of Sonic hedgehog specifies position along the antero-posterior axis, and determines the number of digits, while the progress zone model specifies proximo-distal pattern, and it involves a timing mechanism to provide cells with positional information along this axis. The apical ridge at the tip of the limb specifies the progress zone beneath it, and the cells there divide and give rise to most of the proximo distal axis. Because cells are dividing in the progress, zone cells continually leave the zone, and the length of time they spend in the zone determines their proximo-distal positional value. Cells that leave early form proximal regions, while those that leave later, distal structures. A test of this model involved killing cells in the progress with X-irradiation. The irradiated limbs lost proximal regions as initially so few cells left the progress zone, but as the zone repopulated normality returned for more distal regions. This can explain the effect of thalidomide which damages blood vessels and so can cause cell death in the progress zone.

355

S8

VARGESSON N. University of Aberdeen, Aberdeen, United Kingdom. Thalidomide-Induced Teratogenesis: Lessons and Insights into Abnormal Development Thalidomide was used as a nonaddictive, nonbarbiturate sedative and also used to treat morning sickness between 1957–1962. Thalidomide exposure in early pregnancy caused severe malformations to the forming embryo. Amongst the most commonly seen malformations are to the limbs. A striking and broad range of damage results from thalidomide exposure in a short time window of sensitivity ranging from Amelia (no limb), phocomelia (loss or shortening of proximal elements of the limb), radial dysplasia to triphalangeal thumb. Some of the limb elements appear more sensitive to thalidomide exposure than others, for example the radius is one of the most sensitive tissues. However, thalidomide exposure also caused damage to many other tissues and organs including eyes, ears, spine, genitalia, and internal organs including kidneys, GI tract, and heart. Thalidomide has since been demonstrated to have antiinflammatory and antiangiogenic capabilities. Thalidomide has now been shown to be very effective and successful in treating inflammatory conditions such as leprosy and also cancers such as multiple myeloma, though it retains some nasty side-effects including peripheral neuropathy, blood clotting amongst a few. How thalidomide caused such severe damage to the developing embryo, and particularly the limbs, remains a topic of much debate and research. Indeed, many models and theories have been proposed to explain the mechanisms underlying thalidomide embryopathy. The widely accepted models presently, and which are not necessarily mutually exclusive, are through the drugs anti-angiogenic actions, induction of Reactive Oxygen Species/cell death and/or through binding Cereblon, part of a ubiquitin ligase complex, which is hypothesized to misregulate developmental signaling pathways. Thalidomide-induced limb damage can in some cases resemble other nonthalidomide-induced human congenital limb syndromes which has led to some misdiagnoses. Yet, this also allows for the possibility, which will be discussed, that some thalidomide and nonthalidomideinduced limb injuries may share common mechanisms of origin, for example, disturbed angiogenesis resulting in bone formation failure. This hypothesis could shed light on mechanisms of origin of not just thalidomide-induced limb injuries but other nonthalidomide-induced limb malformations.

Birth Defects Research (Part A) 103:351–366 (2015)

356

SYMPOSIUM ABSTRACTS

March of Dimes Symposium Perinatal Outcomes following Assisted Reproductive Technologies (Joint with OTIS) Chairpersons: Kembra L. Howdeshell, National Institute of Environmental Health Sciences and Laxmi Kondapalli, Colorado Center for Reproductive Medicine

S9

GETZ KD1, LIBERMAN RF1, LUKE B2, STERN JE3, DECLERCQ ER4, ANDERKA MT1. 1Massachusetts Department of Public Health, Center for Birth Defects Research and Prevention, Boston, MA, United States, 2Department of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, East Lansing, MI, United States, 3Department of Obstetrics and Gynecology, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States, 4Department of Community Health Sciences, Boston University School of Public Health, Boston, MA, United States. The Occurrence of Birth Defects in Relation to Assisted Reproductive Technologies in the Massachusetts Outcomes Study of Assisted Reproductive Technology (MOSART) Database Objectives: To compare the prevalence of birth defects among births to mothers who conceived using assisted reproductive technology (ART) and those who conceived without ART and to evaluate potential mediation of the associations through plural births. Design: Longitudinal cohort study using a database of live births and stillbirths to Massachusetts residents from September 2004 through December 2010 created via a linkage of data from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System (SART-CORS) and the Pregnancy to Early Life Longitudinal data system. Materials and methods: Births recorded in SART-CORS were classified as ART-exposed; otherwise they were considered unexposed. Births to women who utilized ART previously or who had an indication of infertility were excluded from the unexposed population. Log-binomial regression was used to directly estimate age-adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for cardiac and noncardiac defects overall and for specific defects with at least 11 ART-exposed cases. A causal mediation framework was used to decompose the total effect of ART into the indirect effect mediated by plural birth and the direct effect (i.e., the effect through other undefined pathways). Mediation analyses were performed separately for cardiac and noncardiac defects. The results presented below are based on preliminary data through December 2008. Results: Of 11,695 ART births, 0.82% had a cardiac birth defect compared to 0.52% of the 310,179 unexposed births (aPR= 1.5, 95% CI: 1.2, 1.8). Approximately, 1.8% of ART births had a noncardiac defect compared to 1.3% of unexposed births (aPR=1.2, 95% CI: 1.1, 1.4). More specifically, analyses suggested modestly elevated rates of conotruncal defects, septal defects, gastrointestinal defects, hypospadias and musculoskeletal defects following ART. Mediation analyses demonstrated that plural births explained more than 80% and 50% of the absolute effect of ART on cardiac defects noncardiac defects, respectively. Final analyses will include births through 2010 which may enable mediation analyses for additional defects, analyses of specific ART procedures, and associations with subfertility. Conclusions: Preliminary analyses identified modest increases in risk for some birth defects relative to ART use, mediation results suggest that a much of the increase in risk is attributable to plurality.

Birth Defects Research (Part A) 103:351–366 (2015)

S10

LUKE B. Michigan State University, East Lansing, MI, United States. The Impact of Multiple Gestations on IVF Outcomes Compared to singletons, twins are born 3½ weeks earlier and at 30% lower birth weight; triplets are born seven weeks earlier and at 50% lower birth weight. As a consequence, the risk of infant mortality is more than fourfold higher for twins and 13-fold higher for triplets. In the US between 1960 and 2013, the frequency of twins increased from 1:50 births to 1:29 births, while triplets rose from 1:3,423 births to 1:837 births, due to a combination of childbearing at older ages and the wider availability and use of in vitro fertilization (IVF) and nonIVF assisted reproductive technologies (ART). Among all singleton births, 95% are conceived spontaneously, 4% from nonIVF ART, and 1% from IVF; among twins, this distribution is 60%, 21%, and 19%; and among triplet and higher-order births, it is 23%, 52%, and 25%. Among all live births conceived with IVF in 2012, 58% were singletons, 40% twins, and 2% triplet or higher-order multiples. Historically, multiple embryos have been transferred during IVF treatment to compensate for low implantation rates, which increased the likelihood of a multiple pregnancy. Transferring multiple embryos has been shown to have a negative effect on those that subsequently develop, including subtle reductions in birth weight, even when plurality at six weeks gestation and at birth is the same. Fetal loss early in pregnancy is associated with lowered birth weight, birth weight-for-gestation, and shortened gestation; after the first trimester it is associated with increasing adverse neurological sequelae for the survivors. The Society for Assisted Reproductive Technology first issued clinical guidelines regarding the optimal number of embryos to transfer in 1998; these guidelines have been revised downward in 1999, 2004, 2006, 2008, 2009, and 2013. As a result, there has been a steady decrease in the number of embryos transferred, as well as a dramatic decline in the higher-order multiple rates due to IVF. Between 2004 and 2012, the proportion IVF cycles with single embryo transfer increased from 8% to 21% while transferring three or more embryos fell from 50% to 23%. The goal of contemporary IVF is a singleton infant born at term.

SYMPOSIUM ABSTRACTS

S11

MAK W. Yale School of Medicine, New Haven, CT, United States. Assisted Reproduction and Changes in the Epigenome Assisted reproductive technologies (ART) have helped millions of couples to realize their dream of starting a family. The majority of babies conceived by ART are healthy however, in the last decade, epidemiological studies have shown that these babies are at higher risk of having congenital malformations and rare imprinting disorders. Furthermore, babies conceived by ART are more likely to have adverse perinatal outcomes such as preterm delivery and low birth weight. During ART, gametes and embryos are manipulated in vitro and therefore it is biologically plausible that the epigenome could be affected during this sensitive developmental window. During this presentation, there will be a brief overview of the adverse outcomes affecting infants conceived by ART. This will be followed by a comprehensive review of the literature on whether the adverse outcomes seen are related to changes in the epigenome resulting from ART.

S12 KONDAPALLI LA1,2, BARNHART KB2. 1Colorado Center for Reproductive Medicine, Lone Tree, CO, United States, 2University of Pennsylvania, Philadelphia, PA, United States. Prospective Cohort Study of Autism, Neurodevelopment, and Behavior in Young Children Conceived by Assisted Reproductive Technology (ART): Cause for Concern or Reassurance? Objective: To investigate the association between assisted reproduction and abnormal neurodevelopment, behavior, and autism in young children using novel methodology to reduce selection, referral, and recall bias. Design: Prospective cohort study. Materials and Methods: Patients who conceived by in vitro fertilization (IVF), ovulation induction (OI/IUI) or unassisted (UA) between 2006–2009 were recruited from the University of Pennsylvania and RMA-NJ. As part of a novel in-home study visit, parents completed validated instruments to screen for abnormal language, motor skills, behavior, and autism spectrum disorders in children aged 3–5 years. Participants were stratified by exposure group and appropriate statistical comparisons were performed. Results: Mean maternal age (34.7y), paternal age (36.5y), and Caucasian race were comparable among the three groups. Parental education level and household income was also similar. The majority of children scored within the normal range on developmental and autism screening. Abnormal screening (%) was noted in: 12.3 (IVF), 20.2 (OI/IUI) and 14.4 (UA) of children (p=0.38). No children screened positive for autism. Conclusions: This study demonstrates that the novel in-home visit is feasible and can be implemented to collect high quality, objective data with minimal bias. We were able to achieve balance in parental age, education, household income, and gestational age across groups. In children conceived by ART, growth and development appears to be comparable to unassisted conceptions. Support: NIH T32 HD007440 & 5K12HD001271-15 (LAK), K24 HD060687-01 (KTB).

357

S13

BOULET SL1, MNEIMNEH AS1, ZHANG Y1, CRAWFORD S1, SUNDERAM S1, MCKANE P3, COHEN B2, STONE C4, JAMIESON DJ1, KISSIN DM1. 1Centers for Disease Control and Prevention, Atlanta, GA, United States, 2Massachusetts Department of Health, Boston, MA, United States, 3Michigan Department of Community Health, Lansing, MI, United States, 4 Connecticut Department of Public Health, Hartford, CT, United States. States Monitoring Assisted Reproductive Technology (SMART) Collaborative: Promoting State-Based Surveillance of ART and Infertility The use of assisted reproductive technology (ART) has increased over time, with ART-conceived infants accounting for 1.5% of all US births in 2011. Although infants conceived by ART have been shown to have higher risks for adverse perinatal outcomes compared with spontaneously conceived infants, the public health impact of ART in the US is not well described because comprehensive data on the short and long-term outcomes of infants born after ART are not routinely collected. The States Monitoring ART (SMART) Collaborative was established in 2001 when CDC conducted a pilot project with the Massachusetts Department of Public Health to link data from CDC’s National Assisted Reproductive Technology Surveillance System with information from the state’s vital records database. Since that initial pilot, the Collaborative has expanded to include data from three additional states—Connecticut, Florida, and Michigan—as well as additional data sources, including disease registries and hospital discharge databases. The vision of the SMART Collaborative is to develop a surveillance system to monitor ART maternal and infant health outcomes, to strengthen the capacity for evaluating these outcomes, and to provide information and assistance to improve maternal and perinatal outcomes and programs in participating states. To that end, we are actively pursuing opportunities to broaden membership in the SMART Collaborative to include a larger network of states with high rates of ART utilization in order to establish a largescale surveillance system for monitoring maternal and infant health outcomes of ART. Currently, linked data files are being used for a number of research projects including an evaluation of the association between use of ART and birth defects, a comparison of embryo transfer practices in a state with an infertility insurance mandate versus states without a mandate, and an assessment of pregnancy hospitalizations for women giving birth to an ART-conceived infant. In the future, we hope to use information from the surveillance system along with results from research studies to inform state and national policy decisions related to ART.

Birth Defects Research (Part A) 103:351–366 (2015)

358

SYMPOSIUM ABSTRACTS

Reactive Oxygen Species, Oxidative Stress, and Redox Signaling in Developmental Toxicology Symposium Chairpersons: Jason M. Hansen, Brigham Young University and Louise M. Winn, Queen’s University

S14

HALES BF. McGill University, Montréal, QC, Canada. Oxidative Stress and Redox Signaling in Toxicology Redox or reduction-oxidation reactions occur when an electron is transferred from a reducing agent/donor to an electron-deficient free radical or oxidant. Oxidants, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), are formed as normal products of cell metabolism. Mitochondria are a primary site of ROS production but nearly all enzymes that utilize molecular oxygen as a substrate produce ROS. Nitric oxide synthases form RNS in cells. Environmental exposures, to radiation, drugs, or chemicals in air, food and water, serve as an additional source of oxidants. ROS/RNS are important in normal cell proliferation, migration, differentiation, inflammation, immune function, and cell death, as well as in the stress response. Oxidative stress is associated with an increase in the production of oxidizing species or a significant decrease in the effectiveness of antioxidant defenses. Antioxidant defenses consist of low molecular weight antioxidants (e.g. reduced glutathione, vitamins C and E), antioxidant proteins (e.g. thioredoxin, glutaredoxin, and metallothioneins), and enzymes (e.g. superoxide dismutases, catalase, peroxiredoxins, and glutathione peroxidases). Redox homeostasis is established by maintaining the balance between pro- and antioxidative processes. When oxidants outweigh antioxidants, damage is caused to DNA, proteins, and lipids. Oxidants induce the formation of multiple DNA lesions, including DNA breaks and modified bases, such as 8-hydroxydeoxyguanosine (8-oxodG) and 8-hydroxyguanosine (8-oxoG). Damage to amino acids may be irreversible or reversible. The oxidation of protein sulfhydryl groups may inactivate enzymes involved in crucial metabolic reactions or disturb the function of redox sensitive transcription factors, altering gene expression. Lipid peroxidation results in the breakdown of polyunsaturated fatty acids to reactive small molecular weight products, such as 4-hydroxynonenal (4-HNE), that also play a role in signaling. Common life-style exposures, to ingredients in cigarette smoke, ethanol, or drugs such as acetaminophen, induce oxidative stress. Oxidative stress and redox disturbances are strongly associated with normal aging and a number of diseases, ranging from neurodegenerative diseases to cancer, inflammatory diseases and heart failure. Substantial evidence has also accumulated to invoke changes in redox homeostasis during organogenesis as a mechanism underlying the birth defects induced by a variety of teratogenic exposures. Supported by CIHR.

Birth Defects Research (Part A) 103:351–366 (2015)

S15

HARRIS C1, SANT KE2, HANSEN JM3. 1University of Michigan, Ann Arbor, MI, United States, 2University of Massachusetts, Amhurst, Amhurst, MA, United States, 3Brigham Young University, Provo, UT, United States. Developmental Toxicants That Alter Conceptal Redox States Produce Differential Effects on the Thiol Proteome The molecular mechanisms of many birth defects remain an enigma. If there is a unifying factor or universal regulator responsible for eliciting malformations, it has not yet emerged. Reports have suggested that many chemical teratogens may act through similar mechanisms by increasing the generation of reactive oxygen species (ROS). Showing that ROS has been generated is possible but a clear description of the mechanistic ROS consequences remains obscure. High throughput proteomic analysis can provide novel insights into mechanistic outcomes by comparison of concentration changes for specific proteins and the types of malformations produced. Studies of the thiol proteome using isotope-coded affinity tags (ICAT) and mass spectroscopy, in conjunction with biochemical, molecular, and functional assays that characterize conceptal redox status, provide novel systems-level views of probable birth defect mechanisms. The known teratogen ethanol (EtOH); leupeptin (LEU), a natural protease inhibitor, and L-buthionine- S,R-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, have all been shown to differentially modify intracellular redox status in cultured rat conceptuses. Embryo (EMB) and visceral yolk sac (VYS) were evaluated separately because these tissues respond very differently to chemical insults and oxidative stressors. Observed alterations in concentrations of ICAT-labeled proteins varied greatly between treatment groups and between the EMB and VYS. Ethanol caused an overall decrease in labeled proteins in the VYS but an increase in the EMB. Affected pathways (KEGG) included nuclear import/ export, actin cytoskeleton, ribosome biogenesis, and protein folding. Leupeptin produced general increases in the VYS but protein content was decreased in the EMB. Pathway analysis revealed significant changes in pathways related to ribosome biogenesis, glycolysis/ gluconeogenesis and the actin cytoskeleton. Lastly, BSO treatment produced increases in both EMB and VYS with the most affected pathways being the spliceosome, glycolysis/gluconeogenesis, antigen processing, and aminoacyl- tRNA biosynthesis. Functionally, the top pathway changes for all test agents point to disturbances involving a single super-complex consisting of the closely aligned ribosome/ spliceosome complexes and their associated regulatory pathways. Comparisons of this thiol proteomic data against alterations of redox status, nutritive functions, metabolic activity, and gene programming suggest that autophagy, a highly redox-regulated process, may be one common target for different ROS-generating teratogens.

SYMPOSIUM ABSTRACTS

S16

WINN LM. Queen’s University, Kingston, ON, Canada. Reactive Oxygen Species, Embryonic Cell Signaling Pathways, and Teratogenesis In normal embryonic development, cells proliferate extensively, but in a tightly controlled, tissue-specific fashion. Therefore, events that result in aberrant gene expression during development have the potential to cause teratogenesis, including the development of cancer after the child is born. Proto-oncoproteins are key regulators in embryonic development, playing essential roles in differentiation, proliferation and apoptosis. In particular, phosphorylation of certain transcription factors is often a crucial link between embryonic cell signaling and regulation of a wide variety of genes. Reactive oxygen species (ROS) generated by many physiological processes affects signal transduction cascades by altering the activities of certain protein kinases and transcription factors. In order to maintain proper cell signaling, it is likely that a number of ROS detoxifying processes maintain a threshold level of ROS inside the cell. However, an increase in ROS production may lead to excessive signals to the cell as well as direct damage to key components in signaling pathways. Using the anticonvulsant drug valproic acid and the environmental pollutant benzene as examples, this talk will focus on the links between oxidative stress, embryonic signaling pathways, and aberrant development.

359

S17

WELLS PG1,2, MILLER-PINSLER L2, BHATIA S1, DRAKE D1, SHAPIRO AM1. 1Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada, 2 Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Reactive Oxygen Species (ROS) Formation, Oxidative DNA Damage and Repair in Teratogenesis Birth defects and postnatal neurodevelopmental deficits may be caused by reactive oxygen species (ROS) produced by endogenous embryonic/ fetal pathways, or by in utero exposure to drugs and environmental agents like phenytoin, benzo[a]pyrene (B[a]P), methamphetamine, ethanol, methanol, thalidomide, and ionizing radiation (IR). ROS formation may result via multiple pathways including embryonic prostaglandin H synthase (PHS)-catalyzed bioactivation of teratogens (phenytoin, B[a]P, thalidomide), and induction of NADPH oxidases (ethanol, methanol). The embryopathic nature of ROS is suggested by reduced DNA oxidation and embryopathies following pretreatment with exogenous polyethylene glycol conjugated-catalase or the free radical spin trapping agent phenylbutylnitrone, and similarly respectively decreased or increased embryopathies in transgenic or mutant mice overexpressing or deficient in endogenous catalase (phenytoin, ethanol). The distinct pathogenic role of physiological levels of ROS-initiated oxidative damage to DNA, as distinct from oxidation of fetal proteins and lipids, or from ROS-mediated signal transduction, is revealed by increased postnatal neurodevelopmental deficits in untreated knockout progeny deficient in the DNA repair protein oxoguanine glycosylase 1 (OGG1). DNA repair-deficient knockout progeny (p53, atm, ogg1, csb) are similarly more susceptible than wild type littermates to embryonic/fetal brain DNA oxidation, epigenetic modifications (ethanol), and teratogenesis caused by in utero teratogen exposure (phenytoin, B[a]P, IR, methamphetamine, ethanol). Similarly in culture, conditional knockout embryos deficient in the breast cancer 1 (BRCA1) protein, which regulates several DNA repair pathways including those for oxidative lesions, exhibit enhanced DNA oxidation and embryopathies caused by ethanol and methamphetamine, while brca1 knockout progeny exposed to ethanol in utero exhibit enhanced neurodevelopmental deficits. The BRCA1 studies corroborate the pathogenic importance of oxidative DNA lesions, and reveal an important developmental role for BRCA1 in protecting the embryo from oxidative stress. Numerous protective antioxidative proteins and DNA repair proteins like OGG1 are upregulated by nuclear factor-E2-related factor 2 (Nrf2) in response to oxidative stress, and this upregulation and protection against neurodevelopmental deficits caused by in utero exposure to methamphetamine were lost in Nrf2 knockout progeny, indicating a developmentally important role for Nrf2. The balance between embryonic/fetal pathways for ROS formation vs. ROS detoxification and DNA repair constitutes an important biochemical determinant of risk. (Support: CIHR)

Birth Defects Research (Part A) 103:351–366 (2015)

360

SYMPOSIUM ABSTRACTS

S18

HANSEN JM1, CHAR RE1, CROFTS BJ1, HARRIS C2. 1Brigham Young University, UT, United States, 2University of Michigan, Ann Arbor, MI, United States. Dysregulation of the Redox Proteome in Teratogenesis: Mediation through Nrf2 Activation Many different teratogens are potent inducers of oxidative stress, a term that has historically been defined as an accumulation of oxidizing equivalents that outnumber cellular reducing equivalents resulting in macromolecule damage and eventual cell death. Our view of chemical-induced oxidative stress is evolving to include variations in redox states as a potential modulator of cellular signaling. Sublethal exposures that change intracellular redox couples can alter redox-sensitive signaling and result in cellular dysfunction. As such, regulation of specific redox states is critical to support normal developmental signaling. Our work has demonstrated that embryonic redox potentials (primarily described through the glutathione [GSH] couple) fluctuate during various periods of development. Stagespecific redox fluctuations are conserved over various species, including during zebrafish, chick, and mouse development. These changes to intracellular redox environments correlate to changes in protein redox states and are thereby likely to alter protein function. Utilizing various approaches to evaluate the developmental redox proteome, observations demonstrate that specific proteins shift redox states as development ensues, suggestive of a unique level of regulatory control of development. Influences that alter redox states could prove very damaging during development and thus, prevention of redox shifts may serve to inhibit faulty signaling, cell dysfunction and unfavorable developmental outcomes. Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) is a transcription factor that regulates the inducible expression of numerous phase II and antioxidant enzymes systems. Our work shows that Nrf2 activation protects embryos from prolonged redox imbalance. Utilizing a redox-sensitive FRET probe (RedoxFluor) as a live cell indicator of oxidative stress, Nrf2 activation with dietary and synthetic activators protects against prolonged periods of intracellular redox imbalance from teratogen exposure, suggesting that Nrf2 could be a potential preventative target to reduce the incidence of teratogenesis. As a proof of principle, valproic acid (VA) causes oxidative stress and neural tube defects. Mouse embryos pretreated with an Nrf2 inducer drastically reduced VA-induced GSH oxidation, protein oxidation and the incidence of neural tube defects. These data support a nutritional means to prevent or reduce the incidence of birth defects caused by exogenous exposures.

Birth Defects Research (Part A) 103:351–366 (2015)

Public Affairs Symposium Microbiomes: An Underappreciated Organ for Teratologists (Joint with INA, NBTS, and OTIS) Chairpersons: Lori L. Driscoll, Colorado College and Carl L. Keen, University of California, Davis

S19

SLUPSKY CM. University of California, Davis, Davis, CA, United States. Measuring the Impact of Diet and Environment on Infant Metabolism and the Microbiome The long- and short-term health benefits of breast-feeding have long been recognized. Indeed, breast-feeding is associated with lower incidences of necrotizing enterocolitis and diarrhea in early life, in addition to lower incidences of inflammatory bowel diseases, type-2 diabetes, obesity, and cardiovascular disease later in life. The mechanism by which breast-feeding imparts these protective measures is poorly understood partly due to a lack of available analytical methods to measure the comprehensive effects of feeding practices on infant metabolism. Previously, we reported profound differences between breast-fed and formula-fed infants on growth trajectory, immunological development, succession of the gut microbiome and metabolism that suggests that early imbalances in the pediatric microbiome may influence the development of diseases and disorders in adulthood. It is unknown whether the difference between breast feeding and formula feeding is related to the specific diet used, or whether other diets or formula additives will cause the same effect. To investigate the response of different diets on the gut microbiome and host metabolism, fecal microbial ecology, measured through 16s rRNA sequencing, and comprehensive metabolic profiling of serum, urine, and feces measured through 1H NMR metabolomics, have been analyzed in the context of high and low protein formula diets, and with the addition of probiotics. These results will be discussed in an effort to highlight the links between diet, development of the infant microbiome, host metabolism, and health.

SYMPOSIUM ABSTRACTS

361

S20

S21

Up to 40% of newborns are exposed to perinatal antibiotics, either directly with intravenous ampicillin and gentamicin for early-onset sepsis, or indirectly with administration of maternal intrapartum antibiotic prophylaxis (IAP). In Canada and the US, these treatments patterns adhere to clinical practice guidelines for the prophylaxis of vaginal Group B Streptococcus (GBS) and caesarean section (CS) delivery. With rising rates of CS delivery and GBS colonization during pregnancy, IAP has become a routine part of the birthing process in North America. However, these practices are not universal in Norway, Denmark, Australia and the UK. While effective in preventing early-onset neonatal sepsis, maternal GBS prophylaxis has been linked to amoxicillin-resistant late-onset E. coli infections in infants. Longer-term, infant antibiotic use has been associated with childhood obesity, asthma, and allergy, conditions linked to gut microbiota aberrancies during early life. The presentation will draw from data on gut microbiota profiles of 198 healthy term infants in the Canadian Healthy Infant Longitudinal Development (CHILD) pregnancy cohort study. In the CHILD cohort, maternal IAP exposures and birth method were documented from hospital records and breastfeeding was reported by mothers. Infant gut microbiota were characterized by Illumina 16S rRNA sequencing of faecal samples at 3 and 12 months. IAP for Group B Streptococcus prophylaxis or prelabour rupture of membranes was administered to 21% of mothers; another 23% received IAP for elective or emergency CS. Infant gut microbiota community structures at 3 months differed significantly with all IAP exposures, and differences persisted to 12 months for infants delivered by emergency CS. Taxon-specific composition also differed, with the genera Bacteroides and Parabacteroides underrepresented, and Enterococcus and Clostridium over-represented at 3 months following maternal IAP exposure. Compositional differences were especially evident following IAP with emergency CS, with some changes persisting to 12 months, particularly among nonbreastfed infants. Intrapartum antibiotics in CS and vaginal delivery are associated with infant gut microbiota dysbiosis, and breastfeeding modifies some of these effects.

The neonate is exposed to the maternal vaginal microbiota during parturition, providing the primary source for normal gut colonization, host immune maturation, and metabolism. These early interactions between the host and microbiota occur during a critical window of neurodevelopment, suggesting early life as an important period of cross talk between the developing gut and brain. As perturbations in the prenatal environment such as maternal stress increase neurodevelopmental disease risk, disruptions to the vaginal ecosystem could have significant and long-term consequences for the offspring. During this talk, I will describe a series of experiments to examine the hypothesis that changes in the vaginal microbiome are associated with effects on the offspring gut microbiota and on the developing brain. Using multivariate modeling, we identified broad changes to the maternal vaginal environment that influence offspring microbiota composition and metabolic processes essential for normal neurodevelopment. Maternal stress altered proteins related to vaginal immunity and microbiota composition. Transmission of a stress-altered vaginal microbiota altered colonization in neonates and resulted in long-term disruption of gut microbiota composition in these offspring. Further, altered microbiota composition in the neonate gut corresponded with changes in metabolite profiles involved in energy balance, and with region- and sex-specific disruptions of amino acid profiles in the developing brain. Lastly, I will discuss results from experiments examining whether the early prenatal stress phenotype is transferrable to unexposed offspring by seeding with stress-altered vaginal microbiota. Taken together, these results identify the vaginal microbiota as a novel mode of transmission by which maternal stress may contribute to reprogramming of the developing brain that may predispose individuals to neurodevelopmental disorders.

KOZYRSKYJ A. University of Alberta, Edmonton, AB, Canada. Impact of Intrapartum Antibiotic Prophylaxis and Other Perinatal Interventions on the Infant Gut Microbiome

JASAREVIC E. University of Pennsylvania, Philadelphia, PA, United States. Maternal Stress and the Neonate Gut Microbiome: Effects on Early Life Programming and Neurodevelopment

Birth Defects Research (Part A) 103:351–366 (2015)

362

SYMPOSIUM ABSTRACTS

S22

CRYAN J, DINAN T. University College Cork, Cork, Ireland. Microbiota-Gut-Brain Axis: From Neurodevelopment to Behavior There is a growing appreciation of the relationship between gut microbiota, and the host in maintaining homeostasis in health and predisposing to disease. Bacterial colonisation of the gut plays a major role in postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Individually, these systems have been implicated in the neuropathology of many CNS disorders and collectively they form an important bidirectional pathway of communication between the microbiota and the brain in health and disease. Over the past five years substantial advances have been made in linking alterations in microbiota to brain development and even behaviour and the concept of a microbiota-gut brain axis has emerged. Moreover, it has become clear that diet is one of the most potent ways to modify microbiota composition. Animal models have been essential in moving forward this frontier research area. In order to assess such a role we use studies involving, germ free mice and early-life microbiota manipulations and finally probiotic administration in adulthood. We assess neurochemical, molecular, and behavioural effects following these manipulations. Our data show that the gut microbiota is essential for normal stress, antidepressant, and anxiety responses. Moreover, microbiota is essential for both social cognition and visceral pain. Finally, there are critical time-windows early in life when the effects of microbiota on brain and behaviour appear to be more potent. Manipulation of the microbiota in early life by cesarean delivery, antibiotics, or stress leads to long-lasting effects on brain and behavior. Our data also demonstrates that these effects may be mediated via the vagus nerve, spinal cord, or neuroendocrine systems. Such data offer the enticing proposition that specific modulation of the enteric microbiota by dietary means may be a useful “psychobiotic”-based strategy for both stress-related and neurodevelopmental disorders ranging from depression to autism.

Birth Defects Research (Part A) 103:351–366 (2015)

Genetic and Environment Interactions of Common Malformations Symposium Chairpersons: Suzan L. Carmichael, Stanford University and John M. Graham, Cedars-Sinai

S23

BACINO CA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States. Developmental Etiopathogenesis of Clubfeet: Genetic and Environmental Factors Congenital talipes equinovarus is the most common musculoskeletal congenital birth anomaly observed in humans, and seen as frequently as 1/700 in liveborn children. Congenital talipes equinovarus is a multifactorial disorder hence the combination of genetic and environmental factors are known contributors to this developmental abnormality. The etiology of this birth defect is therefore heterogeneous and many epidemiological and genetic studies have been undertaken to pinpoint the specific molecular causes and contributing environmental factors. As of today, a number of genes involved in limb patterning like PITX1, HOXA, HOXD, TBX4, and RBM10, as well as genes involved in muscle contraction, have been identified as possible players. These genes and pathways provide important clues that will ultimately help us understand the etiopathogenesis that leads to this defect. Among a large number of environmental factors investigated, maternal smoking seems to present the strongest consistent association with this disorder. This presentation will summarize the current knowledge around the genetic and environmental evidence surrounding this common birth defect and highlight the possible mechanisms leading to congenital talipes equinovarus in the general population.

SYMPOSIUM ABSTRACTS

S24

LALANI SR, BELMONT JW. Baylor College of Medicine, Houston, TX, United States. Congenital Heart Defects Cardiovascular malformations (CVM) are an important class of birth defects affecting 0.5–0.7% of all live born infants. Despite important advances over the last decade, the etiology of the vast majority of CVM is unknown. Environmental causes such as maternal diabetes mellitus, phenylketonuria, maternal alcohol use, rubella, and drugs including isotretinoin and lithium are known contributors. Genetic disorders make up the most complex and significant category of causes of CVM. Chromosomal abnormalities detected by conventional karyotyping account for approximately one-tenth of all cases in live born infants. Genomic disorders resulting from instability of regional genomic architecture constitute another important category. There has been enormous progress in the discovery of causative genes for syndromic heart malformations and in rare families with Mendelian forms. The genes identified encode many transcription factors and chromatin regulators important for cardiac patterning. Genomewide sequencing of the coding regions promises to elucidate genetic causation in several disorders affecting cardiac development. Such comprehensive studies evaluating both common and rare variants would be essential in characterizing gene-gene interactions, as well as in understanding the gene-environment interactions that increase the susceptibility to congenital heart defects.

363

S25

TULLY HM1,2, DOBYNS WB1,2. 1University of Washington, Seattle, WA, United States, 2Seattle Children’s Research Institute, Seattle, WA, United States. Infantile Hydrocephalus As a Complex Interplay between Genetic and Environmental Risk Factors Hydrocephalus, characterized by pathologic and progressive accumulation of CSF within the ventricular system of the brain, affects one in 1,000 births and has the potential for major neurodevelopmental morbidity. Infantile hydrocephalus, which develops during the prenatal period or the first year of life, is heterogeneous in nature. Approximately 40% can be classified as acquired: the direct result of an extrinsic event such as intraventricular hemorrhage or bacterial infection, which is often post-natal in onset. The remaining 60% can be viewed as developmental: the consequence of an obstructive malformation of the brain or skull, manifest most often before birth. However, recent evidence suggests that the distinction between developmental and acquired forms of hydrocephalus may not always be straightforward: Very early prenatal events such as hemorrhage can induce obstructive brain malformations, presumably by interfering with early developmental pathways. These induced malformations may be radiographically indistinguishable from those seen in genetic forms of hydrocephalus. Moreover, the tendency to develop hydrocephalus after post-natal hemorrhage or infection may be influenced by genetic factors: recent research suggests that the risk of acquired hydrocephalus is influenced by sex and ethnicity. Here, we review the epidemiology, classification, and pathogenesis of infantile hydrocephalus. We describe the major genetic and environmental risk factors for hydrocephalus as well as the complex interplay between them, with the goal of providing a framework to guide diagnostic workup and direct future research.

S26 CARMICHAEL SL. Stanford University, Stanford, CA, United States. Genetics and Gene-Environment Interaction from the Epidemiologic Perspective Epidemiology focuses on risk factors at a population level. Epidemiologic studies provide clues for further more mechanistic investigation and also provide a means to translate the potential impact of more basic findings to population health. The etiology of most structural malformations (and especially their nonsyndromic forms) is likely multifactorial, i.e., a combination of genetic and environmental factors lead to their development. However, translating the multifactorial model into actual population-level epidemiologic study designs is challenging. During this talk we will discuss some successful examples as well as the challenges and what it may take to overcome them in the future.

Birth Defects Research (Part A) 103:351–366 (2015)

364

SYMPOSIUM ABSTRACTS

The Pregnancy and Lactation Labeling Rule Symposium It’s Here, Now What? (Joint with OTIS) Chairpersons: Christina D. Chambers, University of California, San Diego and Melissa S. Tassinari, US Food and Drug Administration

S27

S30

Abstract not available.

SAUBERAN J. Sharp Mary Birch Hospital for Women and Newborns, Neonatal Research Institute, San Diego, CA, United States. Considerations for Populating the Lactation Section, 8.2

S28 LAFFAN SB. GlaxoSmithKline, King of Prussia, PA, United States. Integrating Animal and Pharmacology Data in the New Label To provide more meaningful information for clinicians, the new Pregnancy and Lactation Labeling Rule requires the inclusion of a Risk Summary, which is a narrative summary of the risks of a drug during pregnancy and lactation based on detailed supporting data. This talk will describe how to incorporate animal and pharmacologic information into risk summaries including a brief overview of the types of data that are considered relevant. The talk will then describe how the data set is incorporated into the label in relation to human risk. For animal data, the risk statement must describe the potential risk for adverse developmental outcomes in humans. To make an assessment of human risk using available data, an integration tool is offered, FDA Guidance for Industry: Reproductive and Developmental Toxicities—Integrating Study Results to Assess Concerns. How the output of the data integration tool is incorporated into risk summary will be discussed. Also, when the drug has a wellunderstood pharmacologic mechanism of action that may result in adverse developmental outcomes, the Risk Summary must explain the mechanism of action and the potential associated risks. Lastly, each section will be addressed for potential applicability of animal data and the need for cross referencing will be explained.

S29 CHAMBERS CD. University of California, San Diego, La Jolla, CA, United States. Clinical Data in the Label: Evaluating Sources and Reliability of Clinical Data The Pregnancy and Lactation Labeling Rule sets a new standard for the presentation of human safety data in the context of clinical considerations and the potential impact of the underlying maternal disease. The required label updates and the creation of new labels will call for scrupulous attention to sources of valid and informative data that can be included in the label. A review of possible sources of those data, including information from pregnancies that occur in the course of clinical trials, ongoing birth defects surveillance studies with prenatal exposure information, pregnancy registries, and data linkage studies, will be presented. Although published data will be of primary interest, the fact remains that for most currently marketed medications in the US there the published human safety data are inadequate or nonexistent. Populating labels in the new format should encourage efforts to seek out high quality information that has already been collected but not yet analyzed or published, and for capturing data from multiple sources of well-designed studies.

Birth Defects Research (Part A) 103:351–366 (2015)

This talk will outline the new lactation labeling rule and will discuss the practical implications for primary label consumers; clinicians and drug information providers. The new label provides breastfeeding risk assessment based on available data. These data include drug and metabolite milk concentrations, technical quality of concentration studies, systemic bioavailability to the infant, and known or predicted adverse effects in breastfed infants or lactating women. Recommendations on minimizing drug exposure in certain situations will also be part of the label. The label won’t provide a risk grade, or use terms like safe or compatible. Nor will the label recommend suitable alternative drugs. Although these labeling changes represent a major improvement, label consumers will need to use judgment and critical thinking when applying concentration data and no data to individual cases. Using specific drug examples, this talk will discuss approaches to take when applying judgment, and will offer recommendations on efficiently navigating the new label contents.

S31 Abstract not available.

SYMPOSIUM ABSTRACTS

365

Cerebral Palsy: History, Mechanisms, and Prevention Symposium Chairpersons: Nigel Paneth, University of Michigan and L. David Wise (ret.)

S32

NELSON KB1,2. 1National Institute of Neurological Disorders and Stroke, NIH (ret), Bethesda, MD, United States, 2Children’s National Medical Center (ret), Washington, DC, United States. Birth Defects and Cerebral Palsy Cerebral palsy (CP) is a group of congenital motor disorders of cerebral origin, occurring in~2/1000 births. Cognitive limitation, seizure disorder, and sensory problems may accompany the defining motor disability. In the past, CP was attributed chiefly to birth asphyxia. Intrauterine exposure to infection/inflammation and fetal growth restriction (FGR) also play roles in CP etiology. Since the earliest controlled studies of etiology in cerebral palsy, and consistently in subsequent investigations, congenital anomalies have been observed more frequently in persons with CP than in comparison groups. In a large population-based study in Western Australia that linked a CP registry with a Birth Defects registry, major birth defects (BD) recognized by age six years had a population attributable fraction of 39% for CP in singletons born at or after 35 weeks gestation (in whom 3/4th of CP arises). The proportion of CP attributable to potentially asphyxiating birth events was 4%, infection/inflammation 3%, FGR 12%. Minor BDs in the absence of major BDs were not associated with CP risk. Defects of the central nervous system, most often congenital microcephaly, were the BD most commonly associated with CP, indicating impaired prenatal brain growth or braindestructive disease. Congenital cardiac lesions were the next most common BD linked with CP risk. Many BDs are not recognized in the newborn period; their ascertainment is related to when and how they are sought. Marked fetal growth retardation is also an important risk factor for CP and other congenital neurologic disabilities. FGR may be related to CP risk chiefly through its association with BDs. Half of growth-restricted term and late preterm singletons with CP had a major BD. The combination of FGR with a major BD was associated with a 30-fold increase in CP risk. BDs ascertained by early childhood markedly overshadow birth asphyxia, infection/inflammation, and FGR, or a combination of these, as predictors of CP in term and late preterm singletons in a developed country. The dominant role of birth defects in cerebral palsy has not been a major focus of CP research in the past but should be in the future.

S33

PANETH N. Michigan State University, East Lansing, MI, United States. The Causation and Prevention of Cerebral Palsy (CP) CP is the commonest severe motor disability of childhood. Population-based registries of CP describe CP prevalence rates from 1.5–2.5/1,000 live births, but a recent US study found a prevalence of 3.2/1,000 school-age children. Premature birth and difficult labours are often seen in the background of CP, but may not be direct causes. Infants experiencing fetal inflammation are more likely both to be born prematurely and to develop CP, and inflammation may contribute independently to both outcomes. Some infants with neurologic signs at birth may have been injured earlier in gestation. Risk for CP increases steadily with declining gestation, and the risk in infants born prior to 28 weeks of gestation is 50-fold higher than at term. An increase in CP due to increased survival of premature infants in developing countries appears to now be leveling off. Among prematures, the most important risk factor is evidence of white matter damage (WMD) on cranial ultrasound images. Some forms of WMD carry a CP risk of around 50%. Chorioamnionitis, transient hypothyroxinemia, and hypocapnea from mechanical ventilation are also risk factors for CP in prematures, but these associations may not all be entirely causal. In term-born infants, low Apgar scores are potent correlates of CP. Absent birth depression, complications of labor do not raise the risk of CP. The proportion of CP attributable to birth asphyxia is between 10–20%. About 5% of CP is from perinatal ischemic stroke. Neonatal hyperbilirubinemia, with kernicteric staining of the brain, can cause CP at any gestational age, but is now rare in developed countries as a result of exchange transfusion, phototherapy, and most importantly, Rhogam therapy. In parts of the world with severe iodine deficiency, children are born with a form of spastic diplegia. Some 10% of children with CP have a brain malformation, often unsuspected without neuro-imaging. Cooling the brain or body in term infants with birth asphyxia and neurological signs can reduce risk of mortality and CP by 25%. MgSO4 given in labor before 32 weeks reduces the risk of CP in prematures as does caffeine administration for apnea.

Birth Defects Research (Part A) 103:351–366 (2015)

366

SYMPOSIUM ABSTRACTS

S34

ROSENBAUM PL. CanChild, McMaster University, Hamilton, ON, Canada. Clinical Diagnosis and Management of Cerebral Palsy Cerebral Palsy (CP) in some ways represents a prototype for neurodevelopmental disabilities. CP means different things to different people. Parents, and people with CP, experience CP as a condition that usually presents life-long developmental and functional challenges. Neurologists and neuroscientists recognize CP as conditions that provide opportunities to understand the links between functional neurological impairments and underlying neuroanatomy and neurophysiology. Epidemiologists need to understand what CP “looks like” in order to be able to ascertain and count it, in order to discern causal pathways associated with it. This conceptual presentation will begin with an overview and interpretation of the current international definition of CP, and how CP is described clinically. Next, I will present a brief overview of key clinical features of CP and how it is categorized. The talk will then introduce the framework of the WHO’s International Classification of Functioning, Disability and Health (ICF) as the foundation for the rest of the talk. Using the ICF framework I will provide a brief account of traditional thinking about “treatment” and “management”, and discuss the limitations of these approaches. I will follow this critique with an outline of modern thinking about “childhood disability”, and discuss a recent idiosyncratic effort by our research group to graft a series of “F-words” about childhood disability onto the ICF framework. The goal will be to reframe CP to encourage people to recognize the importance of child and family development, strengths and achievements – even in the face of impaired development and function. The talk will conclude by identifying the as-yet unaddressed realities of adults with CP, about whom we know very little, and from whom there are still many lessons to be learned. In addition to a host of biological, technological and clinical advances in the understanding and prevention of CP (to be addressed by other speakers), there are a number of significant conceptual developments in the fields of “disability” and “health” that have important implications for how we think and talk about CP and how we approach “treatment” and “management”. It is hoped that these ideas will be of interest to listeners.

Birth Defects Research (Part A) 103:351–366 (2015)

S35

JOHNSTON MV. Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States. Neuroprotection and Treatment of Cerebral Palsy Cerebral palsy (CP) is an umbrella term for a variety of disorders of tone and motor function that are due to brain damage in the fetal or perinatal period. The primary causes of CP are deprivation of oxygen and blood flow or infection and inflammation in the fetus or neonate. These two causes, infection/inflammation and hypoxia/ischemia can also occur together. In general terms, the fetus or premature infant prior to 34 weeks gestation is most likely to have injury to the developing white matter, while the older infant is more likely to have the most severe injury from these insults in the developing neuron-rich gray matter regions such as the cerebral cortex and basal ganglia. In developed countries, about 15–20% of CP is caused by neonatal asphyxia at term, but in resource poor areas the number is as high as 50%. In the laboratory, two major mechanisms of injury have been identified: 1) glutamate mediated excitotoxicity and activation of nNOS producing nitric oxide and cell death following hypoxia-ischemia; and 2) inflammation trigered activation of microglia associated with nNOS activation and cell death. Three approaches are being used to protect or rescue the developing brain from damage causing CP: 1) clinical use of moderate cooling for 3 days for term infants with asphyxia; 2) experimental administration of antiinflammatory drugs to infants after asphyxia or experimental delivery via nanoparticles in animal models; 3) experimental administration of cell-based therapies in animal models to repair white matter injury. Moderate cooling for asphyxia has become standard of care in most developed countries and three large clinical trials have demonstrated its ability to increase survival without CP by 40%.

Birth Defects Research (Part A) 103:367–374 (2015)

TERATOLOGY SOCIETY WORKSHOP ABSTRACTS

(Presenter designated by underlined author.)

Birth Defects Research (Part A) Clinical and Molecular Teratology 103:367–374 (2015)

368

WORKSHOP ABSTRACTS

Student and Postdoctoral Lunch Workshop: Transitioning from Graduate School, to Postdoctoral Fellow, to First Job

Regulatory Neurodevelopmental Testing: New Guiding Principles for Harmonization of Data Collection and Analysis Workshop (Joint with NBTS)

Chairpersons: Jeffrey H. Charlap, WIL Research and Christine P. Curran, Northern Kentucky University (Abstract is an overview of the workshop; all authors will be presenting)

Chairpersons: Alan M. Hoberman, Charles River and Abby A. Li, Exponent, Inc.

W1

CURRAN CP1, CHARLAP JH2, SLEDZIK CS4, KLEINSTREUER NC3. 1Northern Kentucky University, Highland Heights, KY, United States, 2WIL Research, Ashland, OH, United States, 3 ILS/NICEATM, Research Triangle Park, NC, United States, 4 BrandMuscle, Cleveland, OH, United States. Professional Development Workshop: Transitioning from Graduate School, to Postdoctoral Fellow, to First Job Four speakers representing academia, government, and industry will provide insights and advice on career transitions and professional development for graduate students, postdoctoral fellows and other early career professionals. The topics to be covered include: Teaching and Learning: What you need to know no matter what career path you take; GLPs: what are they, why are they important, and how to use them to get great data; Networking in the Digital Age: How to use online and in-person tactics to advance your career; and Career Transitions: How to build bridges and not burn them. Participants will learn about basic pedagogical techniques that can be applied both in the classroom and during scientific presentations to a variety of audiences. Different learning styles will also be explained along with strategies to maximize communication effectiveness. The principles of Good Laboratory Practice and their importance will be explained using case studies and history. Career-building presentations will address the importance and power of new networking techniques such as LinkedIn when combined with fundamental relationship-building tactics. Learn best practices for digital networking to leverage your research and advance your career. Learn how to manage smooth career transitions from student to postdoc, postdoc to independent researcher, independent researcher to group leader, and beyond. Special emphasis will be placed on the importance of developing long-term research plans with realistic goals, and the benefits and challenges of maintaining multi-scale collaborations.

Birth Defects Research (Part A) 103:367–374 (2015)

W2

BAILEY F. Pest Management Regulatory Agency, Health Canada, Ottawa, ON, Canada. Reexamining the Developmental Neurotoxicity Study and Risk Assessment The rodent Developmental Neurotoxicity (DNT) study paradigm has evolved over time with the most recent test guidelines updated in 2007 with the introduction of Organization for Economic Co-operation and Development (OECD) guideline 426. Over the past four years, a joint USEPA-PMRA intergovernmental group has been working to create an internal guidance document for regulatory reviewers in both countries. As a NAFTA-inspired multi-governmental initiative that involved consultation with both governmental and nongovernmental stakeholders, this initiative was undertaken to provide better context to key parameters necessary for the review of a DNT study, not only for the individual behavioural tests, but for their integration into the weight of evidence for the entire study and for the ultimate assessment of hazard and risk. Over the past year, efforts have focused on providing the content for the internal guidance document. A breakdown of the regulatory importance of the major themes and the key outputs is provided in order to inform external stakeholders of key elements identified in this internal evaluation guidance document.

W3 SHEETS LP. Bayer CropScience, Research Triangle Park, NC, United States. Evaluating Data Variability for Neurobehavioral Measures: How Much Is Too Much? Neurobehavioral testing is a foundational component of studies designed to assess developmental toxicity and developmental neurotoxicity with pharmaceuticals and chemicals, including pesticides. Computer-automated tests of motor activity and the acoustic startle response are common methods of such studies. Variability of neurobehavioral endpoints is often relatively high, especially at early stages of development, which undermines reviewer confidence in study results and has impacted the interpretation and application of additional safety factors for infants and children. Thus, it is important to control environmental factors that contribute to variability and to understand what is normal or excessive for different endpoints. This presentation will set the stage for the workshop, by using new data comparisons of neurobehavioral endpoints from different types of guideline studies to illustrate how variability in control animals is increased, due to study design requirements, relative to what is achievable under optimal conditions. This presentation will illustrate how to examine variability in the context of particular stages of development, including how to differentiate between excessive variability and highly-consistent results that are inherently more variable.

WORKSHOP ABSTRACTS

W4 BOWERS WJ1,2. 1Health Canada, Ottawa, ON, Canada, 2Carleton University, Ottawa, ON, Canada. New Insights into Analysis of Highly Variable Data: Motor Activity As a Case Study Motor activity (MA) testing is a requirement of both EPA and OCED DNT guidelines as well as the new OECD extended one-generation reproductive toxicity test guideline. Thus, MA will continue to play an important role in children’s health risk assessment. The test guidelines are relatively nonspecific about test procedures and data reporting, and high variability in MA data directly impacts interpretation of both study conduct reliability as well as decisions on whether there are effects on the developing nervous system. Similarly, shortcomings in the reporting of MA data from testing laboratories also contribute to uncertainty about test results. This presentation will discuss the type of data that needs to be reported so that regulators can assess the quality of activity data including “normal” activity patterns for the strain, species and equipment. This presentation will provide guidance on expected MA variability under required testing conditions based on recent retrospective analysis of control data from DNT studies submitted to Health Canada. The impact of software and equipment settings on activity of control animals at different developmental stages will be presented. The use of different covariates that can address MA variability will be compared.

369

W5

RAFFAELE KC1, LAU E2, VIDMAR T3, LI A2. 1OSWER, US EPA, Washington, DC, United States, 2Exponent, Inc., San Francisco, CA, United States, 3BioSTAT, Kalamazoo, MI, United States. Hypothesis-Driven Testing and Analysis: Auditory Startle As a Case Study DNT studies conducted for regulatory purposes incorporate multiple endpoints that vary in the specific parameters measured as well as the metrics used to evaluate results. Regulatory guidelines provide flexibility in study design, placing responsibility on the individual investigators to precisely define the hypothesis being tested and design appropriate analyses. Available equipment can record multiple parameters, not all of which convey biologically meaningful information. Thus it is useful to focus the study design on detection and analysis of those effects whose biological significance is meaningful in the risk assessment context. Although general guidance has been provided, practical recommendations on implementation of such approaches have been limited, and differences in guideline specifications suggest different biological hypotheses that could be tested within the general guidance provided. For example, the new OECD extended 1-generation study includes a test of auditory startle habituation at PND 24 in 1 male or 1 female/litter. OECD DNT guidelines specify some test of sensory and motor function at two ages in 1 male AND 1 female/litter (i.e. a test of habituation is not required). Analysis of auditory startle data could include treatment, sex, trial block, and day as potential factors in a hierarchical model; analyses of these data could include multiple main effects as well as a many levels of interactions, for multiple measured parameters. Using auditory startle as an example, types of parameters typically measured, ways in which measured parameters may be summarized or combined, and the utility of various types of information in evaluating biological effects of treatment will be explored. Discussion will focus on identifying parameters that have biological relevance for use in risk assessment, and how that and other practical considerations (e.g. type of device) might impact evaluation and graphical and tabular presentation of data. This is an abstract of a proposed presentation and does not reflect the policy of the US Environmental Protection Agency.

Birth Defects Research (Part A) 103:367–374 (2015)

370

WORKSHOP ABSTRACTS

W6

MOSER VC1, HOFSTRA A2. 1US Environmental Protection Agency, Research Triangle Park, NC, United States, 2Syngenta Canada Inc, Guelph, ON, Canada. Standardization of SOPs to Evaluations: Impacts on Regulatory Decisions Using Learning and Memory As Case Studies In an era of global trade and regulatory cooperation, consistent and scientifically based interpretation of developmental neurotoxicity (DNT) studies is essential, particularly for nonstandard assays and variable endpoints. Because there is flexibility in the selection of test method(s), standardization can be especially challenging for learning and memory tests required by US EPA and OECD DNT test guidelines (chemicals and pesticides) and recommended in ICH prenatal/postnatal guidelines (pharmaceuticals). No one cognitive test is clearly superior, yet detection of treatment effects may depend on this choice. An understanding of the purpose behind the tests and expected outcomes is critical, and attention to elements of experimental design, conduct, and reporting can improve data collection by the investigator as well as accuracy and consistency of interpretation by regulatory evaluators. This understanding also directs which information must be clearly described in study reports. Standard operating procedures (SOPs) may contain important experimental features, but if not clearly reflected in thorough report submissions there may be questions and misunderstandings by evaluators which could impact risk assessments. A practical example of learning and memory tests will be presented to provide insights into important experimental variables, reporting methods, and approaches for data assessments. Cognitive functions most often tested in DNT guidelines studies include associative, positional, sequential, and spatial learning and memory in weanling and adult animals. These complex behaviors tap different brain areas and develop at different rates. The relative involvement of different neural systems depends on the specific task; however, there is considerable overlap across brain areas during the process of acquisition (learning) and consolidation of memory. Evaluation should include integration of treatment data including performance assessments (motor, sensory), control data (concurrent, historical, positive), and additional measures of neuro- or other toxicity. Doing so can empower consistent and defensible risk evaluations. These considerations provide a stronger scientific basis for standard evaluation approaches for review and interpretation of DNT studies. This is an abstract of a proposed presentation and does not reflect US EPA policy.

Birth Defects Research (Part A) 103:367–374 (2015)

W7

LI AA1, GARMAN RH2, KAUFMANN W3, AUER RN4, BOLON B5. 1Exponent Health Sciences, San Francisco, CA, United States, 2 Veterinary Pathology, Murrysville, PA, United States, 3Merck KGaA Global Pathology & Reproductive Toxicology, Darmstadt, Germany, 4Hôpital Saint Justine, Montréal, QC, Canada, 5The Ohio State University, College of Veterinary Medicine, Columbus, OH, United States. Weight of Evidence (WOE) and Benchmark Dose (BMD) Analysis: Brain Morphometry and Startle Behavior As Examples The new OECD 443 extended 1-generation study and also OECD 426 and EPA OPPTS 870.6300 developmental neurotoxicity (DNT) studies have been conducted more frequently for pesticides than other chemicals. Guidelines for these studies include neuropathology and brain morphometry as test article effects on these endpoints may be considered more “severe” than effects in dams. Concerns about increased qualitative (i.e., greater severity) or quantitative sensitivity in offspring have informed DNT regulatory decisions based on the Pest Control Products Act (PCPA) in Canada or the Food Quality Protection Act (FQPA) in the United States, and in Europe may lead to classification as a developmental toxicant. The aforementioned guidelines focus on evaluating offspring, with limited analysis of adults. Therefore, conclusions about relative sensitivity of offspring vs. adults must compare the WOE from other adult toxicity studies with any changes in DNT parameters. Improved selection of brain morphometry measures that take into account brain cytoarchitecture coupled with the systematic collection of maternal toxicity data strengthens the scientific basis for WOE assessments. Although direct effects on the nervous system cannot completely be ruled out, decreases in morphometric measurements and brain weight of juveniles in conjunction with decreased dam and/or juvenile body weights can be interpreted as evidence that the brain alterations are related to a more general effect on growth rather than a specific neurotoxic effect. Absolute morphometric values can be compared with relative values based on brain weight or brain volume in evaluating whether or not alterations might be related to a more general effect on growth. Appropriate selection of a BMR for DNT endpoints also impacts interpretation of relative sensitivity. Statistical and toxicological evidence support setting BMR s for behavior endpoints higher than the default 5% level used by European Food Safety Authority (EFSA). These guiding principles for evaluating WOE and selecting BMR can improve risk assessment decisions and BMD analysis for DNT data.

WORKSHOP ABSTRACTS

371

ILSI HESI Workshop Contraception in Clinical Trials: From Animal Data to the Patient Chairpersons: Jane Stewart, AstraZeneca Pharmaceuticals and Belen Tornesi, AbbVie Inc.

W8

BRESLIN WJ. Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, United States. How Do We Use Animal Data to Determine Contraception for Subjects in Clinical Trials? In early drug development there is a high level of concern for the unintentional exposure of the embryo/fetus (EF) prior to information being available concerning the drug’s potential benefit vs. risk. To address the risk side of the equation, steps can be taken to either restrict women of child bearing potential (WOCBP) from clinical trials or prevent pregnancies in WOCBP through contraception use and pregnancy testing. In September 2014, the Clinical Trials Facilitation Group of the European Heads of Medicines Agencies published recommendations related to contraception and pregnancy testing in clinical trials. This guidance applies contraception practices based on three levels of risk, with risk determined, in part, on the results of nonclinical genotoxicity and EF developmental toxicity studies. Prior to the EU guidance, members of the pharmaceutical industry developed their own internal operating algorithms for the application of contraception practices in clinical trials. This presentation will discuss the application of nonclinical toxicity data in the determination of the need for, type, and duration of contraception recommended for clinical trials during drug development. Factors affecting the decisions around contraception use and duration will include the availability of nonclinical data, type of nonclinical toxicity observed (i.e., genotoxicity, spermatogenic injury, teratogenicity, embryolethality, fetal weight), margin of safety, toxicokinetics, gender of clinical trial subject, and effectiveness of the birth control methods.

W9

DESAI M. AbbVie, North Chicago, IL, United States. Contraception in Clinical Trials: From Animal to Patient For new investigational medical product (IMP) entering in first-inhuman (FIH) clinical trials, there is usually no information about the risk to unborn child following exposure to IMP during early stages of pregnancy. In general, only male or women of no child-bearing potential would be allowed to participate in FIH studies. Women of child-bearing potential (WOCBP) would be included only after detailed evaluation of IMP-related factors such as, availability of sensitive animal species, findings from preclinical toxicology studies, genotoxicity/genetic damage at level of germ cells and/or conceptus and known information from the class of agent and Clinical Trialrelated factors such as, fertility of study population, anticipated exposure of IMP, study duration, and seriousness of the underlying disease. Three possible clinical scenarios arise from these evaluations for WOCBP: 1) if there is a suspected human teratogenicity/ fetotoxicity risk based on results of initial developmental range finding studies and/or embryo-fetal development studies in one species (rat or rabbit usually) then, the use of highly effective contraception with lower user dependency and monthly pregnancy testing is required. In addition, male contraception (condoms, vasectomy) are strongly recommended for male participants with WOCBP partners. Also, in absence of preclinical animal data, it should be assumed that a demonstrated or suspected human teratogenicity/fetotoxicity exist. 2) if there exist a possible human teratogenicity/fetotoxicity risk based on unequivocal preclinical studies or known class effect of the drug then, the use of highly effective contraception and additional pregnancy testing is required. The frequency of pregnancy testing could be influenced by clinical trial related factors described above; at a minimum before initiation of therapy with IMP and once upon discontinuation. Additional recommendations for male contraception could be considered. 3) if there is an unlikely human teratogenicity/ fetotoxicity risk based on no findings in preclinical data or no known class effect then, the use of an acceptable effective contraception is generally required with pregnancy testing done only as needed. Additional recommendations for male contraception are generally not required.

Birth Defects Research (Part A) 103:367–374 (2015)

372

WORKSHOP ABSTRACTS

W10

CARLSON GF. AstraZeneca, Gaithersburg, MD, United States. Assessment of Drug Interaction Potential of Novel Medicines with Hormonal Contraceptives Unintentional exposure of an embryo or fetus before information is available concerning the potential benefits versus potential risks of a new chemical entity raises concern for women of child bearing potential (WOCBP). When WOCBP are included in early clinical development, especially without nonclinical developmental toxicity studies, prevention of pregnancy is of utmost importance. ICHM3(R2) defines effective methods of birth control as capable of achieving a failure rate of less than 1% a year. Given the popularity of systemic hormonal methods for birth control, and the potential for drug-drug interactions, ICHM3(R2) requires that “information regarding the product under evaluation and it potential effect on the contraceptive method be addressed”. In addition, it is recommended that the study protocol should contain detailed information on the level of contraception, the possibility for an interaction between the novel compound and hormonal contraceptives, the frequency of pregnancy testing, and the duration of the need for contraceptive measures. To fulfill this important obligation, projects are guided by a decision tree which requires, as a minimum, assessment of in vitro data pertaining to cytochrome p450 induction and, where necessary, in vivo clinical data examining the interaction of cytochrome substrate compounds such as midazolam with the NCE. Depending on the results of the in vitro and in vivo clinical studies, the decision tree may ultimately require a formal assessment of DDI potential between the NCE with ethinyl estradiol (EE) prior to acceptance of EE containing methods in the intended WOCBP clinical trial. Use of this decision tree schematic defines acceptable methods of birth control throughout the preclinical reproductive toxicity data acquisition phase and ensures WOCBP are informed of which highly effective hormonal birth control methods are suitable for the intended clinical trial. Understanding hormonal contraceptives and their risk for failure allows for their inclusion as early as possible in clinical trials, thus hastening the enrollment of WOCBP.

Birth Defects Research (Part A) 103:367–374 (2015)

Mechanisms of Postnatal Reproductive Development/Puberty and Methods for Evaluation Workshop Chairpersons: Susan B. Laffan, GlaxoSmithKline and Kary E. Thompson, Bristol-Myers Squibb

W11

STOKER TE. US Environmental Protection Agency, Research Triangle Park, NC, United States. Improving the Assessment of Endocrine Disrupting Chemicals (EDC) Effects on Puberty During puberty, key developmental events occur that are critical for normal adult male and female reproductive maturation. Recent studies raised concern that exposure to environmental chemicals alter the normal progression through puberty and lead to impaired reproductive function in the mature animal. Advances or delays in puberty are dependent on the class of chemicals examined and the developmental timing of exposure. For this reason, the US EPA included male and female pubertal assays in their Tier 1 Endocrine Disruptor Screening Program (EDSP). These assays are reliable for detecting changes in the timing of puberty and provide insight into the mode of action involved. These assays are a critical part of the overall Tier 1 battery providing valuable in vivo information for a weight of evidence approach. At the same time, these assays are resource intensive (both in time and animals used) limiting the number of chemicals that can be examined. To better prioritize the chemicals to be examined for potential effects on pubertal development, it is of value to develop a series of molecular and in vitro approaches that are predictive of potential adverse effects. Accordingly, our laboratory and others have examined a number of approaches and evaluated endpoints that may have value as predictors of EDC activity. For example, there is a distinct increase in GnRH secretion and pulsatility prior to puberty. This critical process can be examined directly in vitro using a neuronal cell line or by ex vivo methods. In addition, a number of growth factors are important for the progression of puberty and we are currently developing cell-based assays to screen for the impact of a test chemical on the regulation of this process. In related studies, we are also evaluating the potential permanent effects of pubertal delays in the male rat, as EDC-induced reductions in testosterone during puberty have been reported to alter subsequent adult male sexual behavior. Therefore, a better understanding of the impact of EDCs on molecular targets and the potential permanent outcomes should provide the basis for smarter testing and result in a concomitant reduction in the utilization of resources.

WORKSHOP ABSTRACTS

W12

LAFFAN SB. GlaxoSmithKline, King of Prussia, PA, United States. In Vivo Assessments of Puberty with Focus on Female Rodent Model The mechanistic biology in neuroendocrine control of the onset of puberty (GnRH pulse generator modulation) in animal models, including a comparison of different signaling effectors between males and females and among species will be reviewed. In vivo assessments in nonclinical models in the context of a toxicity study will be discussed: what treatment periods are required to potentially affect puberty, what endpoints are feasible for each species, and when these endpoints should be evaluated. Then, considerations to interpretation will be highlighted using examples; inherent variability in the model, potential for technical interference, effect of body weight gain and a weight-of-evidence approach, including assessments of growth. The talk will then move to a focus on assessing pubertal timing in the female rodent. A comparison of endpoints in the untreated juvenile female Wistar Han rat including onset of vaginal opening, first estrus as assessed via cytology of vaginal lavage, serum hormone levels, estrous cyclicity and histology of the developing female reproductive tract. Finally, a case study investigating a potential effect on pubertal timing in the female rodent will be discussed.

373

W13

THOMPSON KE1, BUSS N2, STEWART J3. 1Bristol-Myers Squibb Company, New Brunswick, NJ, United States, 2Medimmune, Gaithersburg, MD, United States, 3AstraZeneca, Macclesfield, Cheshire, United Kingdom. Assessing the Effect of a Long-Acting GLP-1 Agonist on Onset of Puberty in Rats Glucagon-like peptide-1 receptor (GLP-1r) agonists improve glycemic control and body weight in adults and with increasing need to manage type II diabetes in periadolescent patients, paediatric investigatory plans (PIPs) have been agreed for several GLP-1r agonists for diabetic children from 10 years of age. However, there was regulatory concern for potentially accelerated puberty due to increased testis weights in monkeys across various GLP1-r agonists, triggering a request to evaluate these drugs for effects on puberty in support of pediatric development. The various PIPs include plans to study puberty in several species including mouse, rat, and dogs. In this work, a GLP-1r agonist, pharmacologically active in rodents, was evaluated in male and female rats over the critical period of sexual maturity for endpoints including vaginal patency (VP)/preputial separation (PPS), reproductive organ weights, microscopic evaluation of the gonads, hormones, and estrous cycles as well as routine endpoints to assess growth. Due to the known confounding effects of reduced body weight on onset of puberty in rats, both vehicle and pairfed control groups were included for comparator purposes. In females, VP was delayed in GLP-1r agonist-treated rats relative to controls as assessed either by chronological age or body weight on day of attaining criteria, suggesting delay of VP is independent of drug-induced effects on body weight. Estrous cycles, serum hormones, and reproductive organ histopathology and weights were generally comparable in all groups. Similarly in males, GLP-1r agonist exposure was associated with delays in PPS relative to both ad libitum-fed and food-restricted controls. Interestingly, serum LH and GH were elevated relative to food-restricted controls. However, there were no associated impacts on the age at which microscopic evidence of active testicular spermatogenesis was observed. Considered together, no evidence was found that administration of a GLP1-r agonist to rats accelerates sexual maturation in males or females.

Birth Defects Research (Part A) 103:367–374 (2015)

374

WORKSHOP ABSTRACTS

W14

LEE MM. University of Massachusetts Medical School, Worcester, MA, United States. Clinical Perspectives on Environmental Influences on Pubertal Timing In humans, puberty is heralded by maturation of the adrenal gland and activation of the hypothalamic-pituitary-gonadal axis. These dual hormonal systems induce the physical signs of sexual development that are assessed by sexual maturity staging, namely breast and pubic hair development in girls; and testicular growth, genital maturation, and pubic hair growth in boys. A secular trend towards an earlier onset of puberty has been reported worldwide in girls and less consistently in boys. A parallel temporal trend has been observed in the prevalence of obesity, which is also associated with accelerated somatic growth and earlier onset of adrenarche and breast development. It has been speculated that these trends in growth and timing of sexual maturation are associated with environmental exposures to endocrine disrupting compounds that act as obesogens and stimulate breast development through estrogenic properties. These endocrine disrupting compounds perturb endocrine signaling and action and can interfere with sex steroid pathways. This talk will review the recent trends in age of pubertal onset and provide examples of environmental chemicals that have been associated with earlier onset of puberty in girls. In boys, the data is more controversial with variable shifts in age of pubertal timing in population studies, whereas environmental epidemiology studies have reported both delayed puberty and early puberty associated with chemical exposures. These effects appear to be compound specific and may depend on whether the chemical has estrogenic, antiandrogenic, or androgenic effects. Potential mechanisms by which environmental chemicals affect sexual development and the public health implications of these shifts in pubertal timing will be discussed.

Birth Defects Research (Part A) 103:367–374 (2015)

Birth Defects Research (Part A) 103:375–401 (2015)

TERATOLOGY SOCIETY PLATFORM ABSTRACTS

(Presenter designated by underlined author.)

Birth Defects Research (Part A) Clinical and Molecular Teratology 103:375–401 (2015)

376

PLATFORM ABSTRACTS

Student/Postdoctoral Fellow Platform Session 1 Organized by the Student Affairs Committee, Chairperson: Jason M. Hansen, Brigham Young University and Stephen B. Harris, Stephen B. Harris Group

1

BURTON T1,2, HOWE-PATTERSON M2, RAMCHANDANI S2, OZOLINS TRS1. 1Queen’s University, Kingston, ON, Canada, 2Analytics for Life, Kingston, ON, Canada. Latent Teratogen-Induced Heart Deficits Are Unmasked Postnatally with Mathematical Analysis and Machine Learning on ECG Signals Congenital heart defects (CHD) are the most common birth anomaly. Although CHD may resolve spontaneously within the first year of life, the long-term consequences on postnatal heart function are unknown. Our contention is that while CHD may resolve, these hearts will function differently than hearts that did not have defects at parturition. To experimentally test this hypothesis, we have developed a rat model in which pregnant rats are administered a chemical that induces a high incidence of both structural and function defects in offspring. After eight weeks these deficits resolve to the point that control and treated offspring are indistinguishable using standard echocardiography. Our hypothesis is, that using more rigorous ECG analysis, we will be able to identify latent functional anomalies in treated offspring. Rats were treated in such a way as to induce a high incidence of CHD in offspring. Dams delivered naturally and heart structure and function were assessed in female pups using echocardiography on postnatal day (PND) 4, 21, and 56. At PND 56 radiotelemetry units were implanted into 9 treated rats and 8 control rats. Two weeks postsurgery, telemeters were activated and ECG recordings collected for 5 min, every 12 min continuously for two weeks. 50,000 data points per rat were each transformed into unique three-dimensional phase space and machine learning used to create predictive algorithms capable of identifying differences in heart function between control and treated rats. These results demonstrate that teratogen-induced CHD that resolve postnatally and appear normal by conventional measures are, in fact, different from teratogen naïve hearts. By extrapolation, this suggests that individuals with resolved CHD may carry insidious pathologies that may manifest in later life and this may warrant more concerted clinical follow-up. That structural anomalies and functional deficits may occur independently of one another in postnatal life suggests this may also occur in the neonate. If true, current preclinical studies may be unable to detect chemicals that only induce functional deficits. Funded by: Southern Ontario Smart Computing Innovation Platform (SOSCIP) and Ontario Centres of Excellence (OCE) Medical Sciences Proof-of-Principle (MSc PoP).

Birth Defects Research (Part A) 103:375–401 (2015)

2 Abstract withdrawn.

PLATFORM ABSTRACTS

3

LOVELY CB, NORRIE JL, HENEGAR T, SWARTZ ME, EBERHART JK. University of Texas at Austin, Austin, TX, United States. Zebrafish Genetic Screens Identify Ethanol Susceptibility Loci Fetal Alcohol Spectrum Disorders (FASD) are highly variable, with facial and neural phenotypes being common. Some of this variability is thought to be due to genetic predisposition, yet we know very little about the loci contributing to FASD variability. We have used genetic screens in zebrafish to identify and characterize mutations generating susceptibility to ethanol teratogenesis. By exposing zebrafish embryos to concentrations of ethanol that do not cause defects in wild type embryos, we are able to identify dominant modifiers of ethanol teratogenesis. In a “shelf screen” of zebrafish mutants, we identified the Bone Morphogenetic Protein (Bmp) pathway as being ethanol sensitive. Ethanol-treated Bmp-pathway mutants have variable defects to the lower jaw and palate. Analysis of the BMP family in a human dataset linked BMPR1B to similar craniofacial phenotypes in FASD. The nature of the ethanol-induced jaw defects is consistent with defects to the pharyngeal endoderm. Using transgenic and genetic mosaic analyses, we have shown that the pharyngeal endoderm requires Bmp signaling for proper morphogenesis and blocking Bmp signaling during this endoderm requirement results in severe defects to the lower jaw. In addition to lower jaw defects, we have shown that loss of Bmp signaling results in palatal defects due to reductions in gata3 expression. Preliminary data suggests that ethanol-treatment of Bmp-pathway mutants may disrupt both endoderm morphogenesis and palatal development. From a forward genetic screen, we have isolated two mutants, au15 and au26, that display ethanol-induced phenotypes strikingly similar to those observed in the ethanol-treated Bmp-pathway mutants. Jaw defects are observed in ethanol-treated au15 mutants, while au26 mutants exhibit ethanol-induced palatal defects. This suggests that they work in ethanol-sensitive pathways regulating craniofacial development. Currently, au15 and au26 are being mapped and sequenced via whole genome sequencing. Our data suggest that au15 may function downstream of Bmp signaling, while au26 appears to act parallel to Bmp signaling. We are currently determining how both au15 and au26 might interact with the Bmp pathway. Overall, these data demonstrate that zebrafish is a useful model to identify and characterize gene-ethanol interactions and this work will directly inform our understanding of FASD.

377

4

EL HUSSEINI N, HALES B. McGill University, Montréal, QC, Canada. The Role of p53 Signalling in Hydroxyurea Embryotoxicity Hydroxyurea (HU), an anticancer agent and potent teratogen, is used as a model drug to study the embryonic stress response during organogenesis. Previously, we demonstrated that HU activates a DNA damage response (DDR) pathway in regions of the gestation day (GD) 9 mouse embryo that are associated with malformations (Toxicol Sci. 2013 133(2):298–308). The p53 tumor suppressor gene is a possible downstream effector of this pathway. P53 plays an important role in embryonic development; however, its function in response to teratogen-induced stress is not well understood. We hypothesize that HU activates p53 and that p53 mediates downstream events leading to cell death in regions of the embryo where malformations are observed. To test this hypothesis, saline (Control-CO) or HU (low dose - LD: 400 mg/kg; high dose- HD: 600 mg/kg) was administered intraperitoneally to GD9 timed pregnant CD-1 mice; dams were euthanized 3 h later, embryos extracted and samples prepared for the analysis of gene and protein expression. qRT-PCR analysis revealed that p53 mRNA levels were not changed by HU treatment. Western blot analysis demonstrated that HU induced a significant, dosedependent increase in p53 protein concentrations [LD: 2.8 ±0.1; HD: 4.0 ± 0.1, n=4-5, fold change ±SEM] and in phospho-p53 (ser15) [LD: 3.0 ±1.0; HD: 5.5 ±0.7, n=5]. The expression of p53 target genes was determined to assess whether the transcriptional activity of p53 was increased by HU treatment. The expression of Fas, the cell surface receptor related to apoptosis [LD: 6.0 ±1.9, HD: 4.5 ±0.8; N=3, fold change ±SEM] and tp53inp1, a proapoptotic protein that is also involved in autophagy [LD: 6.4 ±0.3, HD: 6.4 ±0.1; n=3, fold change ±SEM] were both significantly upregulated. Together, these data show that p53 signalling is activated in response to a teratogenic stress during organogenesis. This activation triggers upregulation of apoptosis and autophagy related factors. Funded by CIHR MOP57867. NELH is the recipient of an award from CIHR-REDIH.

Birth Defects Research (Part A) 103:375–401 (2015)

378

PLATFORM ABSTRACTS

5

LI Q1, KAPPIL M1, LI A2, DASSANAYKE PS2, DARRAH T3, FRIEDMAN AE4, FRIEDMAN M4, LAMBERTINI L1, LANDRIGAN P1, STODGELL CJ4, AAGAARD K5, SCHADT E1, MURRAY J6, CLARK EB7, DOLE N8, CULHANE J9, SWANSON J10, VARNER M7, MOYE J11, KASTEN C12, MILLER RK4, CHEN J1, NATIONAL CHILDREN’S STUDY CONSORTIUM11. 1Ichan School of Medicine, Mt. Sinai, New York, NY, United States, 2 University of Illinois, Chicago, Chicago, IL, United States, 3Ohio State University, Columbus, OH, United States, 4University of Rochester School of Medicine and Dentistry, Rochester, NY, United States, 5Baylor School of Medicine, Houston, TX, United States, 6 University of Iowa, Iowa City, IA, United States, 7University of Utah, Salt Lake City, UT, United States, 8University of North Carolina, Chapel Hill, NC, United States, 9The Children’s Hospital of Philadelphia, Philadelphia, PA, United States, 10University of California, Irvine, Irvine, CA, United States, 11National Institutes of Health, Bethesda, MD, United States, 12US Food and Drug Administration, Silver Spring, MD, United States. Exploring the Associations between microRNA Expression Profiles and Environmental Pollutants in Human Placenta from the National Children’s Study (NCS) The in utero environment plays a critical role on health outcomes of the offspring later in life; of which, the placenta is a principal component in this environment. The objective of this study was to assess alterations in miRNA expression by known environmental toxicants measured in placental samples collected from the National Children’s Study (NCS) birth cohort. This study analyzed villous samples from 110 term placentas collected within 6 hours of delivery from singleton vaginal deliveries. MicroRNA expression profiling of 654 miRNAs was conducted using the nCounter Analysis System by NanoString Technologies. The organic pollutants dichlorodiphenyldichloroethylene (DDE), bisphenol A (BPA), congeners of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs), and the toxic metals mercury (Hg) and lead (Pb) were measured in these placentas. A moderated t-test was first used to identify a panel of differentially expressed miRNAs, which was then further analyzed using generalized linear models. Placental miRNA expression levels were highly variable, with 112 miRNAs consistently expressed in >30% of the samples. Out of the top ten most abundant miRNAs (mir-517a, mir-125b, mir-517c/ mir-519a, mir-720, mir-181a, mir-126, mir-522, mir-23a, mir-100, and mir-24), four miRNAs (mir-517a, mir-517c, mir-522, mir-23a) are located within the imprinted placenta-specific C19MC cluster. The toxicant levels detected in placenta samples were low, but they fell within the range observed in previous studies in western industrialized countries. A positive association between congener PBDE209 and miR188-5p and an inverse association between PBDE99 and let-7c were observed. Positive associations were also observed between miR-1537 expression and total PCBs as well as specific congeners 52, and 101. High levels of Hg and Pb were associated with significant changes in multiple miRNAs, many of them belonging to the let-7 family that has been implicated in multiple disease outcomes including cancer. We did not observe any associations between expression of miRNA and placental DDE or BPA levels. This is the first study linking exposure to environmental toxicants and microRNA expression in placentas with normal deliveries. Our results suggest that placental miRNA profiles may function as sensors for in utero exposures to toxic environmental chemicals. (Supported in part by NIH-LOI-2-BIO-18.)

Birth Defects Research (Part A) 103:375–401 (2015)

6

KOLEVA PT1, KIM JS2, GUTTMAN DS3, SEARS MR4, BECKER AB5, MANDHANE PJ1, SUBBARAO P6, TURVEY SE7, SCOTT JA2, KOZYRSKYJ AL1, INVESTIGATORS CHILD STUDY8. 1 Department of Pediatrics, University of Alberta, Edmonton, AB, Canada, 2Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada, 3Cell and Systems Biology, University of Toronto, Toronto, ON, Canada, 4Department of Medicine, McMaster University, Hamilton, ON, Canada, 5Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada, 6Department of Pediatrics, University of Toronto, Toronto, ON, Canada, 7Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada, 8Canadian Healthy Infant Longitudinal Development Study, Hamilton, ON, Canada. Impact of Maternal Overweight during Pregnancy on the Newborn Gut Microbiome Introduction: Obesity in pregnancy alters women’s gut and breast milk microbiota and potentially interferes with the transmission of maternal bacteria to the infant gastrointestinal tract. Elucidation of the influence of maternal obesity on the development of infant gut microbiota and, in turn, as a modifier of child health is a research priority. The aim of this study was to assess the impact of maternal prepregnancy overweight status on infant meconium and fecal microbiota. Specific emphasis was put on the Lactobacillales an order of bacteria whose members become more abundant in intestine and vagina during the third trimester of pregnancy. Methods: This study comprised a subset of 57 mothers and their full-term infants from the Winnipeg site of the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Microbiota of meconium and feces collected at 3-4 months were characterized by Illumina sequencing of the hyper-variable V4 region of the 16S rRNA gene. Measures of the mother’s anthropometry prepregnancy and infant diet were obtained from standardized questionnaires and hospital records. Wilcoxon test and Spearman’s analysis were applied to investigate for any association between taxon abundance and maternal prepregnancy overweight. Results: Of 57 infant meconium samples, sufficient amplification product to permit sequencing was obtained from 13. The prevalence of prepregnancy overweight mothers was 61% (n=8). Abundance of members of the Lactobacillales increased from birth to the 3-4 month fecal sample (median 0.22 vs 1.06, p=0.03). These taxa were significantly correlated with the abundance of the genus Ruminoccocus (r=0.64 and p=0.02) and the family Veillonellaceae (r=0.73 and p=0.01) in meconium and in fecal samples 3-4 months (r=0.81 and p=0.002, and 0.67 and p=0.01, respectively). Significantly higher ratios of Lactobacillales to Bacteroidaceae (0.04), Lactobacillales to Ruminococcaceae (p=0.04) and Lactobacillalles to Lachnospiraceae (p=0.04) were observed in meconium microbiota following prepregnancy overweight compared to normal weight, but not in samples at the 3-4-month time point. Discussion: To conclude, this study highlights the influence of prepregnancy weight on the microbiota of meconium. Members of the order Lactobacillales were significantly correlated with the abundance of butyrate-producing gut microbial communities in meconium samples.

PLATFORM ABSTRACTS

7

WADHWA DESAI R, AMOSU M, SMITH MA. University of Georgia, Athens, GA, United States. Predicting Pregnancy-Related Cases of Listeriosis through In Vitro Invasiveness and Biofilm Formation

379

8 Abstract withdrawn.

Approximately 20% of listeriosis cases occur during pregnancy. An unusual listeriosis outbreak in 2011 was linked to five L. monocytogenes strains, 147 illnesses and 33 adult deaths, but only five pregnancy-related cases. By comparing characteristics of the 2011 outbreak strains to L. monocytogenes strain 12443, known to cause stillbirths in our animal models, our overall goal is to identify bacterial properties related to adverse pregnancy outcomes. Properties examined in the current study included invasiveness, additivity of mixtures, and biofilm formation which may improve Listeria’s environmental survival and persistence within the host. Our specific aims were: 1) compare in vitro invasiveness of 2011 strains and their mixtures to 12443; and, 2) compare biofilm formation among 2011 strains and mixtures to a positive control strain. Human cell lines representing placenta (BeWo) and liver (C3A) were chosen to determine in vitro invasiveness. Approximately 106 CFU of each 2011 strain (A-E) and their mixtures were incubated for 1hr with either 100,000 BeWo or C3A cells. Cultures were exposed to gentamicin to kill extracellular bacteria, and cells were lysed to enumerate intracellular bacteria. Invasiveness of test strains relative to 12443 were expressed as ratios. To determine biofilm formation, multi-well tissue culture plates were inoculated with 1.5x106 CFU/well of all test strains. After 24 or 48 hours incubation, biofilms were stained, and optical densities (OD) were measured at 600nm. Two 2011 strains (D and E) were 2X more invasive (p

55th annual teratology society meeting.

55th annual teratology society meeting. - PDF Download Free
6MB Sizes 112 Downloads 69 Views