TOXICOLOGICAL SCIENCES, 142(2), 2014, 311 doi: 10.1093/toxsci/kfu220 LOOK INSIDE TOXSCI
From the Editor’s Desk
Editor’s Highlights Biomarker of exposure to mitochondrial toxin: Mitochondria, the bioenergetic organelles, are a prime target of environmental toxicants and genetic predisposition. Several disease states are the result of impaired mitochondrial function. Sanders and colleagues (pp. 395–402) take advantage of the dual genome nature of the mitochondria to demonstrate the utility of mitochondrial DNA as a peripheral biomarker of toxin exposure. Rats were treated with the classical mitochondrial toxin rotenone, and mitochondrial DNA integrity was assessed in blood and skeletal muscle well after mitochondrial function had returned to normal. Moreover, the nuclear DNA found in these peripheral sources did not exhibit any damage, which provided an important internal control. Such an assay could find use in assessing exposure to mitochondrial toxins in human populations. Predicting survival after acetaminophen toxicity: The mechanistic pathway toxicity of acetaminophen (paracetamol) is a staple in toxicology courses. It exemplifies the elegance of Phase I and II metabolism and the trouble of the reactive intermediate. In the clinic, though, it represents a serious problem as a common cause of liver damage. Although most people recover from these exposures, many go on to develop acute liver failure, which is characterized by a widespread loss of key liver functions. Production of bile acids is one of those key functions, and Woolbright and associates (pp. 436–444) demonstrate that sharp increases in one particular bile acid, glycodeoxycholic acid, portends poor clinical outcomes. The authors suggest that monitoring of glycodeoxycholic and other bile acids may represent an important biomarker for predicting survival after acetaminophen overdose.
Assessing cardiovascular toxicity via corporate data sharing: Academic institutions and several government agencies have been struggling to develop robust programs of data sharing. In the paper by Ewart and collaborators (pp. 427–435), several major pharmaceutical companies provide an excellent example of data sharing in a study to determine the utility of a particular preclinical test on cardiovascular outcomes in clinical studies. This systematic analysis from over 100 different small-molecule compounds would not have been possible without the collaborative effort. The results suggested that the telemetered dog model has predictive value for QT interval changes in clinical populations, but not for heart rate and diastolic blood pressure alterations. PCBs and neurological function in infants: Polychlorinated biphenyls (PCBs) have long been suspected to disrupt brain function, and numerous animal studies support this association. However, fewer studies have been conducted in humans and even fewer in infants. In the paper by Berghuis and colleagues (pp. 455–462), the research team measured PCBs in cord blood to determine if PCB levels were associated with impaired neurological development at 3 months of age. Higher summed exposures to PCBs and to several common congeners were actually associated with higher neurological function, both in visuomotor and sensorimotor domains. Only one hydroxylated congener was shown to be associated with negative neurological outcomes. The authors suggest several explanations for these results. One not mentioned by the authors is the fact that many high-quality nutritional sources tend to have higher levels of lipophilic environmental toxicants, such that the PCBs may be an indicator of a high-quality diet and that it is the nutritional status that is driving the improved outcomes.
C The Author 2014. Published by Oxford University Press. V
All rights reserved. For Permissions, please e-mail: [email protected]
311
Downloaded from http://toxsci.oxfordjournals.org/ at Karolinska Institutet University Library on July 16, 2015
It is truly a pleasure to read through the papers slated to appear in each month’s issue. Of course, deciding which articles to highlight continues to pose a problem, but what a great problem to have. Our authors have supplied the readers with a broad range of interesting topics, some of which are highlighted below. You will see excellent articles on safety evaluation of important therapeutics, evaluation of scorpion antivenoms, development of biomarkers of exposure, and toxicological effects of heavy metals and flame retardants. This issue also features a two-part Forum series that provides some insight into how adverse outcome pathway (AOP) models can be developed and implemented. I invite you to Look Inside ToxSci for the best original research in the field of toxicology. —Gary W. Miller
From the Editor’s Desk
Editor’s Highlights Biomarker of exposure to mitochondrial toxin: Mitochondria, the bioenergetic organelles, are a prime target of environmental toxicants and genetic predisposition. Several disease states are the result of impaired mitochondrial function. Sanders and colleagues (pp. 395–402) take advantage of the dual genome nature of the mitochondria to demonstrate the utility of mitochondrial DNA as a peripheral biomarker of toxin exposure. Rats were treated with the classical mitochondrial toxin rotenone, and mitochondrial DNA integrity was assessed in blood and skeletal muscle well after mitochondrial function had returned to normal. Moreover, the nuclear DNA found in these peripheral sources did not exhibit any damage, which provided an important internal control. Such an assay could find use in assessing exposure to mitochondrial toxins in human populations. Predicting survival after acetaminophen toxicity: The mechanistic pathway toxicity of acetaminophen (paracetamol) is a staple in toxicology courses. It exemplifies the elegance of Phase I and II metabolism and the trouble of the reactive intermediate. In the clinic, though, it represents a serious problem as a common cause of liver damage. Although most people recover from these exposures, many go on to develop acute liver failure, which is characterized by a widespread loss of key liver functions. Production of bile acids is one of those key functions, and Woolbright and associates (pp. 436–444) demonstrate that sharp increases in one particular bile acid, glycodeoxycholic acid, portends poor clinical outcomes. The authors suggest that monitoring of glycodeoxycholic and other bile acids may represent an important biomarker for predicting survival after acetaminophen overdose.
Assessing cardiovascular toxicity via corporate data sharing: Academic institutions and several government agencies have been struggling to develop robust programs of data sharing. In the paper by Ewart and collaborators (pp. 427–435), several major pharmaceutical companies provide an excellent example of data sharing in a study to determine the utility of a particular preclinical test on cardiovascular outcomes in clinical studies. This systematic analysis from over 100 different small-molecule compounds would not have been possible without the collaborative effort. The results suggested that the telemetered dog model has predictive value for QT interval changes in clinical populations, but not for heart rate and diastolic blood pressure alterations. PCBs and neurological function in infants: Polychlorinated biphenyls (PCBs) have long been suspected to disrupt brain function, and numerous animal studies support this association. However, fewer studies have been conducted in humans and even fewer in infants. In the paper by Berghuis and colleagues (pp. 455–462), the research team measured PCBs in cord blood to determine if PCB levels were associated with impaired neurological development at 3 months of age. Higher summed exposures to PCBs and to several common congeners were actually associated with higher neurological function, both in visuomotor and sensorimotor domains. Only one hydroxylated congener was shown to be associated with negative neurological outcomes. The authors suggest several explanations for these results. One not mentioned by the authors is the fact that many high-quality nutritional sources tend to have higher levels of lipophilic environmental toxicants, such that the PCBs may be an indicator of a high-quality diet and that it is the nutritional status that is driving the improved outcomes.
C The Author 2014. Published by Oxford University Press. V
All rights reserved. For Permissions, please e-mail: [email protected]
311
Downloaded from http://toxsci.oxfordjournals.org/ at Karolinska Institutet University Library on July 16, 2015
It is truly a pleasure to read through the papers slated to appear in each month’s issue. Of course, deciding which articles to highlight continues to pose a problem, but what a great problem to have. Our authors have supplied the readers with a broad range of interesting topics, some of which are highlighted below. You will see excellent articles on safety evaluation of important therapeutics, evaluation of scorpion antivenoms, development of biomarkers of exposure, and toxicological effects of heavy metals and flame retardants. This issue also features a two-part Forum series that provides some insight into how adverse outcome pathway (AOP) models can be developed and implemented. I invite you to Look Inside ToxSci for the best original research in the field of toxicology. —Gary W. Miller
