The effects of dietary polyphenols on reproductive health and early development.

Human Reproduction Update Advance Access published November 5, 2014 Human Reproduction Update, Vol.0, No.0 pp. 1– 21, 2014 doi:10.1093/humupd/dmu058

The effects of dietary polyphenols on reproductive health and early development† Christina Ly 1,2,*, Julien Yockell-Lelie`vre2, Zachary M. Ferraro3, John T. Arnason 4, Jonathan Ferrier 1,2,4,5, and Andreé Gruslin 1,2,3

*Correspondence address. Tel: +1-613-218-1210; E-mail: [email protected]

Submitted on May 1, 2014; resubmitted on September 30, 2014; accepted on October 16, 2014

table of contents

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Introduction Methods Classification and dietary sources of polyphenols Polyphenol pharmacokinetics and bioavailability Absorption, metabolism and elimination Bioavailability Molecular targets of polyphenols: an overview of their potential beneficial effects Polyphenols and oxidative stress Polyphenols and inflammation Polyphenols and AGEs Potential hazardous effects of polyphenols Fertility and sexual development Fetal health Bioavailability of substrates Dietary intake of polyphenols during pregnancy Human studies and translational potential Conclusion and recommendations for future research

background: Emerging evidence from clinical and epidemiological studies suggests that dietary polyphenols play an important role in the prevention of chronic diseases, including cancer, cardiovascular disease, diabetes and neurodegenerative disorders. Although these beneficial health claims are supported by experimental data for many subpopulation groups, some studies purport that excessive polyphenol consumption may have negative health effects in other subpopulations. The ever-growing interest and public awareness surrounding the potential benefits of natural health products and polyphenols, in addition to their widespread availability and accessibility through nutritional supplements and fortified foods, has led to increased consumption throughout gestation. Therefore, understanding the implications of polyphenol intake on obstetrical health outcomes is of utmost importance with respect to safe consumption during pregnancy. methods: Using relevant keywords, a literature search was performed to gather information regarding polyphenol pharmacology and the molecular mechanisms by which polyphenols exert their biological effects. The primary focus of this paper is to understand the relevance of these findings in the context of reproductive physiology and medicine. †

This manuscript is dedicated to the memory of our co-author Andree Gruslin who passed away in 2014.

& The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected]

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1 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5 2Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1Y 4E9 3Division of Maternal-Fetal Medicine, The Ottawa Hospital, Ottawa, ON, Canada K1H 8L6 4Centre for Research in Biotechnology and Biopharmaceuticals, University of Ottawa, Ottawa, ON, Canada K1N 6N5 5 Bruker BioSpin Corp., Billerica, MA 01821, USA

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results: Evidence from both in vitro experiments and in vivo studies using animals and humans demonstrates that polyphenols regulate key targets related to oxidative stress, inflammation and advanced glycation end products. Although the majority of these studies have been conducted in the context of chronic diseases, such as cancer and diabetes, several of the key targets influenced by polyphenols are also related to a variety of obstetrical complications, including pre-eclampsia, intrauterine growth restriction and preterm birth. Polyphenols have also been shown to influence fertility and sexual development, fetal health and the bioavailability of nutrients.

conclusions: Further research leading to a thorough understanding of the physiological roles and potential clinical value that polyphenol consumption may play in pregnancy is urgently needed to help inform patient safety. Key words: polyphenols / reproduction / pregnancy / molecular targets / beneficial and adverse effects

Introduction

Methods A literature search was performed using the National Center for Biotechnology Information (NCBI) PubMed database. The years covered by the search dated from 1972 to 2014 and no language restrictions applied. Relevant keywords (e.g. polyphenols, pharmacokinetics, pregnancy and fertility) were entered in the search to gather information regarding polyphenol pharmacology and the molecular mechanisms by which polyphenols exert their biological effects. The primary focus of this paper is to understand the relevance of these findings in the context of reproductive physiology and medicine.

According to the Quideau definition, the term ‘polyphenol’ is used to define compounds exclusively derived from the shikimate/phenylpropanoid and/or the polyketide pathway, featuring more than one phenolic unit and deprived of nitrogen-based functionalities (Quideau et al., 2011). Simply, polyphenols may be considered plant-derived and/or synthetic compounds containing one or more phenol structural units. Most polyphenols are glycosylated and may be linked with other phenols, or conjugated with glucuronic acid, galacturonic acid, or glutathione, etc., after metabolism in the body (Tsao, 2010). The bioactivity of polyphenols is as diverse as their many phytochemical structures (Cody, 1988; Fig. 1). As such, polyphenols are classified into major groups such as phenolic acids, stilbenes, lignans and flavonoids, which can be sub-categorized as flavanols, flavonols, flavones, isoflavones, flavanones, anthocyanins and proanthocyanidins. Phenolic acids and flavonoids are the most abundant dietary polyphenols; accounting for roughly one- and two-thirds of the total sources, respectively (Han et al., 2007). Although the content of various polyphenols present in food sources varies, the general distribution and approximate quantities of these compounds in common food items have been summarized in Tables I and II. Since several thousand naturally occurring polyphenols have been identified, this review will focus on those most abundant in the human diet and with the greatest documentation in the literature.

Polyphenol pharmacokinetics and bioavailability Although the health benefits of polyphenols appear generally to be dosedependent, the most abundant polyphenols in the human diet are not necessarily the most bioactive. The bioactivity of each polyphenol depends on the level of its activity (e.g. antioxidant capacity) and the extent to which it is absorbed, distributed and metabolized within, and eliminated from the body (i.e. its pharmacokinetics). Researchers have investigated polyphenol pharmacokinetics in adult subjects by measuring plasma and urine concentrations of known metabolites following single-dose administration of the pure compound or food/beverage of interest (Scalbert and Williamson, 2000; Manach et al. 2004, 2005). There is wide variability in the kinetics and bioavailability for different polyphenols and some information regarding the fate of these compounds remains unclear. Furthermore, due to extensive metabolism by the intestine and liver, the metabolites found in the circulation, urine and target organs often differ from the parent compound (Manach et al., 2004); this adds


Polyphenols (also known as phenolics) are the most abundant dietary antioxidants and are common constituents of many plant food sources, including fruits, vegetables, seeds, nuts, chocolate, wine, coffee and tea. Natural polyphenols have garnered significant interest within the scientific community and public media. This spotlight has mainly resulted from emerging evidence which supports a role for polyphenols in the prevention of degenerative diseases, particularly cancer, cardiovascular disease, diabetes and neurodegenerative disorders (Scalbert et al., 2005a, b). As well, an assumption by some members of the general public is that if a natural health product is made of natural substances, then it should be safe to consume (Ipsos-Reid, 2010). As a result, this has created a real interest from the general population to increase their intake of polyphenols through a variety of sources. These sources include nutraceutical foods (e.g. bran, flax and hemp harts), heritage varieties of foods (e.g. purple potatoes), foods and drinks fortified with nutraceutical extracts (e.g. pomegranate, grape and cranberry), as well as concentrated and diverse sources of polyphenolics in dietary supplements (USA), natural health products (Canada), complementary and alternative medicines (Australia), phytomedicines (EU) and traditional Chinese medicines (Asia). Consequently, these sources are frequently consumed at conception and throughout gestation. Despite the beneficial effects observed in many human subpopulations, evidence from experimental studies raise concerns regarding the potential hazards that excessive polyphenol consumption may have on health (Chavarro et al., 2008; Zielinsky et al., 2010; Jacobsen et al., 2014). One of the most at-risk groups may be pregnant women and their fetuses. Therefore, understanding the influence of maternal consumption of these widely available and used agents on reproductive health is imperative. This article reviews polyphenol pharmacology and summarizes their possible beneficial and/or adverse effects on reproductive health and pregnancy.

Classification and dietary sources of polyphenols

Polyphenols and reproduction

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Figure 1 Chemical structures of selected polyphenols.

another level of complexity when studying biological activity in vitro and in animal models. Therefore, understanding polyphenol kinetics and bioavailability is critical for understanding the health effects of these compounds.

Absorption, metabolism and elimination The physicochemical properties of polyphenols, including molecular weight and extent of glycosylation and esterification, are major determinants of intestinal absorption (Scalbert et al., 2002). Higher molecular

weight polyphenols are less likely to be absorbed in the gut, as are anthocyanins which carry a positive charge (De´prez et al., 2001). As a general rule, polyphenols in the form of esters and glycosides are absorbed less rapidly and less efficiently than aglycones (compounds remaining after hydrolysis of phenolic glycosides and esters) and glucosides (glycosides derived from glucose) (Olthof et al., 2001; Manach et al., 2004). This is because glycosylated polyphenols are hydrophilic, thus unable to passively diffuse through the gut wall until they are hydrolyzed (Scalbert and Williamson, 2000; Crespy et al., 2002; Ne´meth et al., 2003). However, active transport mechanisms have also been shown in vitro

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Table I Major dietary polyphenols and their general distribution in foods. Group

Subgroup

Examples

Major food sources

............................................................................................................................................................................................. Tea leaves21 Red fruit (e.g. strawberries and raspberries), onions17 Virtually all fruit12 Cereal grains20

Epigallocatechin gallate Epicatechin Kaempferol, quercetin Cyanin glucoside Apigenin, chrysin, luteolin Daidzein, genistein Naringenin Hesperetin

Green and black tea11 Most fruits, chocolate2 Onions, broccoli, blueberries6,7,8,9 Highly pigmented fruit5 Parsley, celery6,7,9 Soya and its processed products3,16 Grapefruit14 Oranges14

Stilbenes

Resveratrol

Red wine, red grape juice15,22

Lignans

Secoisolariciresinol Sesamin

Flaxseed13 Sesame seed19

Others

Chlorogenic acid Curcumin Rutin Silibinin

Most fruit, coffee4 Turmeric1 Citrus fruits10 Milk thistle seeds18

Benzoic acids Cinnamic acids

Flavonoids

Flavanols Flavonols Anthocyanins Flavones Isoflavones Flavanones

1 Aggarwal et al. (2007), 2Arts et al. (2000a, b), 3Cassidy et al. (2000), 4Clifford (1999), 5Clifford (2000a, b), 6Crozier et al. (1997), 7Herrmann (1976), 8Hollman and Arts (2000), 9Justesen et al. (1998), 10Karimi et al. (2012), 11Khan and Mukhtar (2007), 12Manach et al. (2004), 13Mazur (1998), 14Mouly et al. (1994), 15Prasad (2012), 16Reinli and Block (1996), 17Shahidi and Naczk (1995), 18Siegel and Stebbing (2013), 19Smeds et al. (2012), 20Sosulski et al. (1982), 21Toma´s-Barberan and Clifford (2000), 22Vitrac et al. (2002).

to carry phenolic glycosides through the intestinal cell wall in the rat jejunum (Ader et al., 1996). Similarly, absorption of polyphenols through the placenta is believed to involve selective transporter mechanisms (Unadkat et al., 2004; Chu et al., 2006); although the identity of these transporters remains to be elucidated. Polyphenols are extensively metabolized by both Phase I and II enzymes of xenobiotic metabolism when passing through the small intestine and again in the liver following first-pass clearance via the portal vein (Donovan et al., 2001; Fisher et al., 2001; Wu et al., 2002). Phase I reactions are primarily carried out by a superfamily of isozymes known as cytochrome P450-dependent mixed-function oxidases (CYPs), which make the molecule more polar and are important to facilitate Phase II conjugation reactions that lead to excretion (Foster et al., 2005). These reactions are highly efficient as evidenced by the absence or trace amounts of free aglycones in circulation after polyphenol consumption (Bell et al., 2000). The identification of conjugated metabolites has only been investigated for a few polyphenols and the data regarding the types of conjugates circulating in the human plasma is limited. Nevertheless, it is known that these metabolites are not free in the blood, but rather extensively bound to plasma proteins, primarily albumin (Boulton et al., 1998), and that the binding affinity of these metabolites to albumin depends on their chemical structure (Dangles et al., 2001). However, the degree of binding to albumin and the effects this has on metabolite rate of clearance and biological activity remains unclear (Manach et al., 2004). Phase I and II enzymes have been identified and are also well characterized in the placenta for their role in drug detoxification (Syme et al., 2004); although their in vivo interaction with polyphenols has not been reported. Nonetheless, in vitro assays and in vivo studies not focused on the placenta have clearly shown that polyphenols can have complex effects on drug metabolism through the activation and inhibition of CYP and Phase II enzyme activity (Anger et al., 2005; Foster et al., 2005; Li et al., 2006;

Kimura et al., 2010). Ultimately, the effects of polyphenols on drug metabolism in the placenta may be similar, but should be investigated directly. Following Phase I and II biotransformation, weakly conjugated polyphenols re-enter circulation, whereas extensively conjugated polyphenols are excreted in the bile and enter the large intestine. The microflora hydrolyze glycosides into aglycones and then metabolizes the aglycones into different aromatic acids, which are well absorbed across the colonic barrier (Scheline, 1991; Knaup et al., 2007). These metabolic pathways are well established in animals, but data are still limited in humans. As such, future research should further identify and quantify microbial metabolites in humans and investigate any differences in polyphenol metabolism amongst individuals depending on differences in their microflora composition and diet. This is of particular importance in the case of active metabolites (i.e. products of metabolism with biological activity) since they may have a physiological effect (Kim et al., 1998). Identification of metabolites unique to the degradation of polyphenols may be useful biomarkers of phenolic intake and help researchers determine the biological activity of specific polyphenol-derived conjugates present in vivo. The elimination profile for each polyphenol is different according to the nature of the compound, as demonstrated in animal studies (Crespy et al., 2003). After ingestion, most dietary phenolic metabolites are rapidly excreted in either urine or bile depending on size and degree of conjugation (Manach et al., 2004). Generally, the extent of urinary excretion is proportional to the maximum concentration of metabolites in the plasma. However, there are some exceptions, as demonstrated for anthocyanins, where urinary excretion percentages are very low relative to the plasma concentrations (Wu et al., 2002). This may be explained by higher biliary excretion or extensive metabolism to currently unidentified metabolites or unstable compounds. Metabolites excreted in the bile and in the intestinal lumen may also undergo bacterial-catalysed


Gallic acid p-Hydroxybenzoic acid Caffeic acid p-Coumaric acid

Phenolic acids

Source

Phenolic acids

..................................................

Benzoic acids

Cinnamic acids

Flavonoids

................................................................................................................................................................

Flavanols

Flavonols

Anthocyanins

Flavones

Isoflavones

Flavanones

..........................................................................................................................................................................................................................................................


Table II Phenolic acid and flavonoid content of selected foods (milligrams/100 g of fresh weight or 100 ml of liquids).

Fruit Blueberry

0.3 –0.7g

Grapefruit

200– 220p 50– 100

u

p

3–16p

h

0.00c p

Raspberry

6 –10

2 –3

Strawberry

2 –9p

1 –3p

25– 500p

h

0.1

80– 100u

Orange

1–7c

c

u

x

0.3 ; 40–100

0.00

40– 50u

0.00x

0.8h

n.d.

0.00n

h

n.d.

26.5h; 160u

0.7h

n.d.

2000u

1.4 i

3.2– 48

n.d.

23– 995

n.d.

n.d.

n.d.

0.6– 12.5c

1.5g; 1.9h

15– 75p; 78.5– 385i

0.00– 0.03n

n.d.

1.8h

15q

0.00n

0.4h; 4– 10p

0.00x; 6h

0.8h

n.d.

0.00n

1.3

q

n

n.d.

0.00n

6.2

q

n.d.

0.00m

0.00– 0.40

n.d.

0.00n

n.d.

n.d.

n.d.

n.d.

n.d.

Vegetables Broccoli Celery Parsley

0.00

0.22 ; 3.5

x

0.08 ; 0.1

h

h

0.00

15 n

0.79

h

m

n.d.

q

Onion

n

p

n

1.3 ; 2– 14 ; 50 p

n.d. h

p

24– 184 ; 216 x

7.6–19.8 ; 35–120

0.00– 9.5

n.d.

n.d.

n

m

Cereal grains 45–130e

Barley

239k

e

Rice

1.6 –260l

20–38

Beverages Black tea

3.2 –3.6o

n.d.

114.30n d

4.05n j

n.d.

0.00n j

Coffee

n.d.

n.d.

0.08

0.10

n.d.

0.00

n.d.

n.d.

Green tea

0.8 –1.2o

n.d.

51.03 –324.20t

2.81– 4.77n

n.d.

n.d.

n.d.

n.d.

Red grape juice

n.d.

n.d.

0.00r

0.69r

0.49r

n.d.

n.d.

n.d.

Red wine

2.2 –3.4v

0.47– 1.1v

11.08 –18.36v

0.77– 2.11v

19.27– 152.98s

0.04– 0.17v

n.d.

2.4a

n.d.

53.49 –108.6f

n.d.

n.d.

n.d.

n.d.

n.d.

37.41w

1.26b

n.d.

0.00b

20–90p

n.d.

n.d.

1.19b

n.d.

0.00b

8– 70p

n.d.

Other Dark chocolate

n.d. q

Soy beans Tofu

73 n.d.

n.d.

n.d., indicates that the value has not been determined. a Achilli et al. (1993), bArai et al. (2000), cArts et al. (2000a), dArts et al. (2000b), eDykes and Rooney (2007), fGu et al. (2006), gSchuster and Herrmann (1985), hHarnly et al. (2006), iHeinonen et al. (1998), jHertog et al (1993), kHoltekjølen et al. (2006), lHuang and Ng (2012), mJustesen and Knuthsen (2001), nJustesen et al. (1998), oLin et al. (1998a, b), pManach et al. (2004), qMattila and Hellstro¨m (2007), rMullen et al. (2007), sNyman and Kumpulainen (2001), tPrice and Spitzer (1993), u Ramful et al. (2011), vRodriguez-Delgado et al. (2002), wSakakibara et al. (2003), xWu et al. (2006).

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6 hydrolysis via b-glucuronidases, which are able to release free aglycones from conjugated metabolites. As a result, aglycones can be reabsorbed in both the intestine and the colon and undergo enterohepatic recycling. In this case, first-pass metabolism and disposition does not result in complete elimination of the substance, but rather significantly increases the elimination half-life (Wu et al., 2011).

Bioavailability

Molecular targets of polyphenols: an overview of their potential beneficial effects Although the molecular mechanisms of action of polyphenols have been extensively characterized in systems such as cancer, diabetes and cardiovascular disease (Vauzour et al., 2010; Bahadoran et al., 2013), their effect on pregnancy-related complications is a new and emerging field of research. The health benefits of polyphenols have been traditionally attributed to their antioxidant properties. However, more recent evidence suggests that polyphenols can also attenuate inflammation and inhibit the formation of advanced glycation end products (AGEs). These mechanistic pathways are summarized in Table III and help explain the beneficial effects of polyphenols demonstrated in other systems. As such, the implications of polyphenols and the effects they have on reproductive health will be discussed here.

Polyphenols and oxidative stress Reactive oxygen species (ROS) and antioxidant enzyme systems are important components of many reproductive processes, including ovarian follicular development, ovulation, fertilization, endometrium receptivity and shedding, placentation, embryonic development and implantation (Al-Gubory et al., 2010). Oxidative stress reflects an imbalance between the generation of ROS/free radicals (e.g. superoxide radical, hydroxyl radical and hydrogen peroxide) and antioxidant defences [e.g. copper –zinc superoxide dismutase (SOD) and manganese SOD] which can result in damage to DNA, proteins and lipids (Sugino et al., 2007). During early pregnancy, there is a natural increase in ROS generation caused by the high metabolic rate of the placenta (Al-Gubory et al., 2010). Consequently, the uterus, embryo and feto-placental unit require adequate defence mechanisms to protect themselves against oxidative damage. These adaptations are considered key events for a healthy pregnancy. Therefore, sufficient antioxidant capacity could prevent or attenuate the severity of those disorders induced by oxidative stress, such as pre-eclampsia (PE), intrauterine growth restriction (IUGR), preterm labour and miscarriage (Burton and Jauniaux, 2004; Myatt and Cui, 2004). Polyphenols are able to directly scavenge free radicals and inhibit metal-mediated free radical formation (Frei et al., 1989; Jovanavic et al., 1996; Brown et al., 1998; Frei and Higdon, 2003). The consumption of polyphenol-rich foods and beverages has been shown to increase plasma antioxidant capacity in humans (Prior et al., 2007) and decrease oxidative stress in vivo and in vitro in human placenta and human placental trophoblasts, respectively (Chen et al., 2012). Compared with endogenous antioxidants, the importance of dietary antioxidants in vivo as oxidant scavengers is considered to be minor due to their lower reduction potentials and bioavailability (Frei and Higdon, 2003). Instead, polyphenols are believed to have a greater role in the prevention of oxidative stress through indirect mechanisms, summarized by Frei and Higdon (2003) to include: (i) inhibition of redox-sensitive transcription factors [e.g. nuclear factor-kB (NF-kB)] (Siddiqui et al., 2008); (ii) down-regulation of pro-oxidant enzymes [e.g. inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2] (Chan et al., 1997; Lin and Lin, 1997); and (iii) induction of Phase II enzymes [e.g. glutathione S-transferase (GST)] (Khan et al., 1992; Lin et al., 1998a, b).


Postprandial plasma concentrations of polyphenols, primarily present as conjugated metabolites, vary greatly depending on the chemical characteristics of the polyphenol and the food source. In humans, maximum plasma concentrations of flavonoids rarely exceed 1 mM, but have been reported to range between 0.1 and 5 mM (Scalbert and Williamson, 2000). Unless the polyphenol is absorbed only after metabolism by the colon, peak concentrations are commonly reached 1–2 h after ingestion and then rapidly decline (Scalbert and Williamson, 2000). Thus, maintaining high concentrations in the plasma requires repeated and consistent intake of the polyphenol (van het Hof et al., 1999; Moon et al., 2000; Warden et al., 2001). Bioavailability refers to the amount of phenolic compounds that enter the circulation upon ingestion. However, what is more physiologically relevant is the amount of polyphenol that reaches the target tissue and is subsequently able to elicit a change in intracellular response. Some studies have reported the concentrations of polyphenols in human tissues, but these data is limited to only a few polyphenols and select tissue types, mainly prostate and breast tissues (Hong et al., 2002; Maubach et al., 2003; Henning et al., 2006). In these studies, polyphenol concentrations in the tissues vary widely between participants and do not directly correlate with plasma concentrations. This finding suggests that caution should be taken when using plasma concentrations as accurate biomarkers of exposure and intracellular activity within the target tissue. Pharmacokinetic studies in rat maternal plasma and fetuses have only been performed for a few substances, including green tea catechins (Chu et al., 2006) and grape seed flavanols (Arola-Arnal et al., 2013). In the study conducted by Chu et al. (2006), dams at 15.5 days of gestation were fed with 166 mg green tea extract tablet (considered moderate dosage) containing various catechins, including epicatechin and epigallocatechin gallate (EGCG). At several time points after administration, blood samples were collected and placental and fetal tissues were obtained. Results showed that maternal plasma concentrations of catechins were 10 times higher than in placenta and 50– 100 times higher than in the fetus. Levels of epicatechin were highest in the plasma while the levels of EGCG were highest in the placenta and fetus. This suggests that epicatechin is well absorbed and distributed in the mother, but not in the conceptus. The opposite phenomenon is true for EGCG, suggesting that EGCG is selectively absorbed and retained by the fetus (Chu et al., 2006). Arola-Arnal et al. (2013) reported that flavanols and their metabolites were widely distributed in both pregnant and non-pregnant rat plasma and tissues. Conjugated forms of flavanols were more abundant in the livers of non-pregnant rats compared with pregnant rats, suggesting that flavanol metabolism is less active during pregnancy. Furthermore, flavanol metabolites were abundant in the placenta and detected at low levels in the fetus and amniotic fluid. Overall, this suggests that these compounds are able to cross the placental barrier and therefore, may have biological effects on the offspring.

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Table III Molecular targets of polyphenols. Target

Biological effect

............................................................................................................................................................................................. Oxidative stress Free radicals

Neutralize free radicals and free radical formation4,13,14,20

Redox-sensitive transcription factors (e.g. NF-kB, AP-1)

Prevent transcription factor binding to DNA26,29,36

Pro-oxidant enzymes (e.g. iNOS, COX-2)

Down-regulate gene expression and enzyme activity7

Phase II enzymes (e.g. GST, GP, catalase, SOD)

Activate enzyme activity22,25,26

Lipoproteins

Attenuate the rate of LDL oxidation ex vivo 1,21,42

Lipids

Decrease lipid peroxidation17,28,38

Inflammation Inhibit gene expression and enzyme activity; prevent COX-mediated PG synthesis19,23,40,41,43

LOX

Inhibit enzyme activity10,24,32

PLA2

Selective inhibition of PLA2 isoforms27,39

iNOS

Down-regulate transcription and translation; inhibit NO production9,16,37

NF-kB

Inhibit activation and downstream signalling (e.g. production of cytokines)3,15,33

PPAR

Activate receptor11,18,44

AGE–RAGE pathway Reactive carbonyl species

Scavenge intermediate products in AGE formation process which inhibits AGE production and cross-link formation2,6,30,34

IKK

Inhibit IKK activity; prevent NF-kB binding to DNA; attenuate AGE-mediated production of TNF-a8,31

NADPH oxidase

Reduce mRNA and protein expression12,35

RAGE

Reduce protein expression5

NF-kB, nuclear factor-kB; AP-1, activator protein 1; iNOS, inducible nitric oxide synthase; COX-1, COX-2, cyclooxygenase-1, 2; GST, glutathione S-transferase; GP, glutathione peroxidase; SOD, superoxide dismutase; LDL, low-density lipoprotein; PG, prostaglandin; LOX, lipoxygenase; PLA2, phospholipase A2; NO, nitric oxide; PPAR, peroxisome proliferator-activated receptor; AGE, advanced glycation end product; IKK, IkB kinase; TNF-a, tumor necrosis factor alpha; NADPH, nicotinamide adenine dinucleotide phosphate; RAGE, receptor for AGE. 1 Anderson et al. (1998), 2Babu et al. (2006), 3Bharrhan et al. (2012), 4Brown et al. (1998), 5Burckhardt et al. (2008), 6Cervantes-Laurean et al. (2006), 7Chan et al. (1997), 8Chandler et al. (2010), 9Chen et al. (2001), 10Chi et al. (2001), 11Danesi et al. (2009), 12Da´valos et al. (2009), 13Frei et al. (1989), 14Frei and Higdon (2003), 15Giorgi et al. (2012), 16Ha¨ma¨laïnen et al. (2007), 17 Hayek et al. (1997), 18Jacob et al. (2007), 19Jang and Pezzuto (1999), 20Jovanavic et al. (1996), 21Kasaoka et al. (2002), 22Khan et al. (1992), 23Landolfi et al. (1984), 24Laughton et al. (1991), 25 Lin et al. (1998a, b), 26Lin and Lin (1997), 27Lindahl and Tagesson (1993), 28Matsumoto et al. (1996), 29McCarty (1998), 30Peng et al. (2008), 31Rasheed et al. (2009), 32Reddy et al. (1991), 33 Romier et al. (2008), 34Sajithlal et al. (1998), 35Sarr et al. (2006), 36Siddiqui et al. (2008), 37Soliman and Mazzio (1998), 38Tijburg et al. (1997), 39Tsao et al. (2012), 40Williams et al. (1999), 41 Yasukawa et al. (1998), 42Yokozawa et al. (2002), 43Yoshimoto et al. (1983), 44Zoechling et al. (2011).

Many of these pathways have been shown to play key roles in the pathophysiology of adverse pregnancy outcomes. For instance, immunohistochemical (IHC) analysis conducted by Vaughan and Walsh (2012) showed that pre-eclamptic placenta displayed almost a 10-fold increase in the p65 subunit of NF-kB localized mainly in the cyto- and syncytiotrophoblasts compared with healthy controls. Many of the gene products stimulated by NF-kB [e.g. corticotropin-releasing hormone, tumour necrosis factor alpha (TNF-a), and interleukin 1beta (IL-1b)] are also elevated, suggesting that increased NF-kB signalling is implicated in the pathogenesis of PE (Goksu et al., 2012). Moreover, IHC analysis of preeclamptic placenta demonstrated a significantly elevated expression intensity of iNOS in trophoblast cells (Schiessl et al., 2005) which is known to lead to increased production of NO-derived oxidants capable of damaging DNA and proteins. Furthermore, expression of the pro-oxidant enzyme COX-2 was shown to be increased in placental syncytiotrophoblasts (Goksu et al., 2012) and neutrophils (Bachawaty et al., 2010). Lastly, placental levels of GST are reduced in PE (Zusterzeel et al., 1999) which is of importance as GST is a major detoxifying enzyme that neutralizes the reactivity of electrophiles and therefore, prevents electrophile-mediated DNA and protein damage.

The antioxidant activity of polyphenols has also been demonstrated in animal models of oxidative stress. Administration of tea polyphenols was reported to attenuate experimentally induced decreases in antioxidant enzyme activities, including infection-associated reduction of SOD (Guleria et al., 2002) and ethanol-associated reduction of glutathione peroxidase (Skrzydlewska et al., 2002a, b) activities. Although the levels of these enzymes have been shown to be lower in pre-eclamptic placental tissues compared with gestational age-matched control placentae from non-pre-eclamptic pregnancies (Vanderlelie et al., 2005), the preventive effects of polyphenol consumption on antioxidant enzymatic activity during pregnancy has yet to be explored. In addition, studies using animal models of atherosclerosis have demonstrated that tea and tea polyphenol administration increases the resistance of lipoproteins to ex vivo oxidation and decreases the rate of low-density lipoprotein (LDL) oxidation ex vivo (Anderson et al., 1998; Kasaoka et al., 2002; Yokozawa et al., 2002). Similarly, assessment of thiobarbituric acid reactive substances, an indicator of lipid peroxidation, in plasma and tissue samples of animal models of cancer and atherosclerosis upon polyphenol consumption supports the antioxidant capabilities of plant polyphenols in vivo (Matsumoto et al., 1996; Hayek et al., 1997; Tijburg et al., 1997). Of


COX-1/COX-2

8

Polyphenols and inflammation Inflammation is required to promote healing and is an immunological defence mechanism by which tissues respond to an insult. Inflammation is characterized by the up-regulation of proinflammatory chemokines, cytokines and other inflammatory mediators. Ovulation, menstruation, implantation and parturition are all inflammatory processes. As such, physiologic inflammatory responses are crucial to reproductive success. In general, there are three immunological phases of a healthy pregnancy which coincide with the first, second and third trimesters. Briefly, the first and third trimesters are proinflammatory phases due to the insults caused by blastocyst implantation and parturition, respectively. Conversely, the second trimester represents a predominant antiinflammatory state since the maternal and feto-placental immune systems are at equilibrium (Mor et al., 2011). To prepare for the immunological events during pregnancy, the human decidua contains a high number of immune cells, including macrophages, dendritic cells, mast cells and natural killer cells (Bulmer et al., 1988; King et al., 1997; Zenclussen, 2005; Mor et al., 2006, 2011). These immune cells secrete proinflammatory agents to regulate trophoblast development and function

during the first trimester (Mor et al., 2011) and stimulate the production of uterine activation proteins during the third trimester (Christiaens et al., 2008). Although depletion of these signalling molecules has serious implications for placental development, implantation and decidualization (Manaseki and Searle, 1989; Greenwood et al., 2000; Hanna et al., 2006), an exaggerated inflammatory response is also a mechanism for disease in preterm labour, PE and other obstetrical complications (Romero et al., 2007). Greater intake of polyphenol-rich foods has been associated with decreased incidence of chronic inflammatory diseases in many subpopulations (Yoon and Baek, 2005). Also, several anti-inflammatory drugs, including Aspirinw and Merivaw, have been derived from or are based on phenolic compounds (Cragg et al., 1997; Belcaro et al., 2010; Fu¨rst and Zu¨ndorf, 2014). Polyphenols are reported to exert their antiinflammatory effects through a variety of molecular targets which can be divided into two pathways: the arachidonic acid (AA)-dependent pathway and the AA-independent pathway. COX, lipoxygenase (LOX) and phospholipase A2 (PLA2) are inflammatory mediators included in the AA-dependent pathway. Activation of these proteins leads to the release of AA (a starting point for the general inflammatory response) and promotes the release of proinflammatory molecules (Nijveldt et al., 2001). Conversely, NOS, NF-kB and peroxisome proliferator-activated receptor (PPAR) promote inflammation through AA-independent pathways. Many polyphenols, including resveratrol and EGCG, have been shown to prevent prostaglandin (PG) synthesis by inhibiting COX-1 and COX-2 at the transcriptional and enzyme level (Yoshimoto et al., 1983; Landolfi et al., 1984; Yasukawa et al., 1998; Jang and Pezzuto, 1999; Williams et al., 1999). PGs are autocrine and paracrine lipid mediators that mediate cervical ripening, stimulate uterine contractions and modulate hemodynamic changes. Generally, increased production of stimulatory PGs is involved in the mechanism leading to preterm labour (Ivanisevic´ et al., 2001). Similarly, an increase in vasocontricting, platelet-aggregating PGs is demonstrated in PE (Friedman, 1988). Despite the physiologically relevant effects that polyphenols have on PG production, their use for the clinical management of preterm parturition or PE has never been investigated. Kaempferol and quercetin were shown to inhibit LOX (Laughton et al., 1991; Reddy et al., 1991; Chi et al., 2001). Normally, LOX activation stimulates eicosanoid production which leads to increased myometrial contractility (Bennett et al., 1987; Smith et al., 2001). Women with preterm labour were noted to have increased concentrations of LOX metabolites in their amniotic fluid, suggesting that these AA-derived metabolites may play a role in the aetiology of preterm birth (Romero et al., 1989). Interestingly, when the COX pathway is blocked by selective flavonoids, the LOX pathway continues to produce mediators of inflammation (Moroney et al., 1988). In such cases, the production of leukotrienes and other proinflammatory cytokines (via LOX activation) may even be accelerated. Therefore, polyphenols, such as curcumin, that can inhibit both the COX and LOX pathways are desirable for treating inflammation (Fiorucci et al., 2001; Hong et al., 2004; Yoon and Baek, 2005). Evidence from in vitro studies suggests that polyphenols exert selective inhibition of various PLA2 isoforms. For instance, quercetin is a strong inhibitor of Group II secretory-PLA2, (s-PLA2), but a very weak inhibitor of Group I s-PLA2 in plasma from septic shock patients (Lindahl and Tagesson, 1993). Furthermore, prophylactic administration of polyphenol-rich


great interest, however, is that increased plasma levels of LDL oxidation and lipid peroxidation are associated with fetal growth restriction and PE (Kharb, 2000; Sańchez-Vera et al., 2005; Qiu et al., 2006; KarowiczBilinska et al., 2007). In theory, sufficient maternal antioxidant status before and during pregnancy may help prevent and/or manage adverse mechanisms intimately related to poor reproductive outcomes and that are also associated with poor dietary habits and oxidative stress. However, results from several clinical trials that have studied the use of antioxidant supplementation, specifically vitamin C and E, as a therapy to improve pregnancy outcome have been unsuccessful. Briefly, vitamin C and E therapy aimed at reducing the risk of PE in women at high risk or low/moderate risk for PE was not effective (Spinnato et al., 2007; Roberts et al., 2010). Instead, women supplemented with these vitamins were at increased risk for developing gestational hypertension and premature rupture of membranes (Conde-Agudelo et al., 2011). High-dose vitamin C and E supplementation for women at risk of PE has also been shown to increase the rate of babies born with a low birthweight (Poston et al., 2006). The unsuccessful use of vitamin C and E supplements may be partly explained by an imbalanced administration of vitamins and/or trace elements (Al-Gubory et al., 2010). As described by the EUROFEDA project (European Research on the Functional Effect of Dietary Antioxidants), no single antioxidant is more essential than another, thus preferentially selecting a specific antioxidant supplement may not be justified (Astley and Lindsay, 2002; Al-Gubory et al., 2010). Furthermore, at higher doses similar to those found in supplements, evidence suggests that vitamins C and E act as pro-oxidants (Rietjens et al., 2002; Poston et al., 2006) which may explain the adverse effects seen with their usage. An alternative approach to prevent adverse pregnancy and birth outcomes associated with oxidative stress is through nutritional intervention by using phytonutrients from fruits and vegetables that are nutritionally balanced and rich in multiple antioxidant vitamins and essential trace elements (Polidori et al., 2009; Al-Gubory et al., 2010). However, more research on the requirements of maternal antioxidant micronutrients for normal fetal growth and development is required and limited at present.

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PPAR. For instance, phenolic compounds found in turmeric, red wine and green tea, have all been reported to have anti-inflammatory roles acting chiefly through PPAR activation (Jacob et al., 2007; Danesi et al., 2009; Zoechling et al., 2011). In addition, polyphenols may up-regulate the expression of other PPAR agonists, including paraoxonase-1 (Khateeb et al., 2010), further contributing to an anti-inflammatory state. Non-steroidal anti-inflammatory drugs are commonly prescribed to treat fever, pain and inflammation. However, their use during pregnancy has been associated with increased risks of embryo-fetal and neonatal adverse outcomes (Antonucci et al., 2012). Consequently, future research needs to highlight and evaluate more effective medicinal strategies with fewer adverse effects. Although the anti-inflammatory properties of polyphenols make these compounds attractive therapeutic candidates in various inflammatory-mediated diseases, more information regarding the effects of polyphenols in the context of pregnancy-related pathology is required. Further understanding of the mechanisms by which polyphenols exert their anti-inflammatory effects as well as information regarding dose and duration of treatment will be useful for future drug and/or nutraceutical development.

Polyphenols and AGEs AGEs are a heterogeneous group of compounds formed non-enzymatically between carbonyl groups of reducing sugars and amino groups of proteins, lipids and nucleic acids (Baynes and Monnier, 1989; Fig. 2). AGE production occurs over a period of months and is part of the natural aging process. However, their formation in vitro is accelerated by high glucose levels, or in the presence of oxidative stress (Miyata et al., 1997) which may explain why the levels of AGEs are more pronounced in diseases, such as PE and diabetes, where oxidative stress and/or high glucose plays a role. AGEs are believed to contribute to disease development by: (i) forming crosslinks with one another; and (ii) activating the AGE receptor (RAGE), a member of the immunoglobulin superfamily of cell surface molecules. Cross-link formation disrupts the physicochemical properties of a tissue by increasing the stiffness of the protein matrix and preventing the normal turnover and degradation of matrix proteins, such as collagen and elastin, by proteolysis (Monnier et al., 1996; Singh et al., 2001). On the other hand, AGE–RAGE interaction mediates cellular injury by triggering a wide range of signalling events that modify the action of hormones, cytokines and chemokines and ROS. Key targets of AGE–RAGE signalling include NF-kB and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Schmidt et al., 1994, 2000; Goldin et al., 2006). Serum levels of AGEs in pre-eclamptic women have been reported to be significantly higher than those in healthy non-pregnant women or healthy pregnant women (Chekir et al., 2006). However, other studies have reported contradictory results where serum AGE levels were not elevated in PE, but other RAGE ligands, including HMGB1 and S100A12, were (Harsem et al., 2008; Naruse et al., 2012). These discrepancies may be explained by the heterogeneous nature of the disease and sample size and population differences between these studies. Nevertheless, there appears to be a general consensus in the literature that the AGE –RAGE system is altered in PE. Pre-eclamptic placentae show significantly higher levels of AGE and RAGE than normal placentae, as detected by IHC and western blot analyses, and these findings positively correlate with the levels of lipid and DNA oxidation in the pre-eclamptic samples (Chekir et al., 2006). Immunostaining of myometrial and omentum tissues taken from non-pregnant, healthy


grape extract was shown to attenuate endotoxin-induced s-PLA2 activity in rats (Tsao et al., 2012), although the activities of specific s-PLA2 groups were not discussed. In patients with PE, decidual, placental and plasma levels of PLA2 are elevated (Jendryczko et al., 1989; Lim et al., 1995; Staff et al., 2003) and plasma levels correlate with the severity of the disease (Lim et al., 1995). As such, it may be useful to investigate therapeutic agents that can decrease levels of PLA2, as seen with polyphenols, in the context of PE. Interestingly, not all PLA2 isoforms are associated with increased inflammation. Group V s-PLA2 has been identified to have a novel anti-inflammatory role in immune complex-mediated arthritis (Boilard et al., 2010), but its interaction with polyphenols has not been reported. In inflammatory diseases, NO is produced in greater amounts and acts as a proinflammatory mediator. Placentae obtained from pregnancies complicated by IUGR and fetal hypoxia displayed increased NO production compared with controls (Tikvica et al., 2008). Moreover, exposure of endothelial cells to pre-eclamptic plasma was found to stimulate NOS activity and increase NO production (Baker et al., 1995). In regards to the AA-independent pathways, flavonoids, including quercetin and apigenin, were found to inhibit the production of NO by down-regulating iNOS transcription and translation in LPS/cytokine-induced cell models of inflammation (Soliman and Mazzio, 1998; Chen et al., 2001; Ha¨ma¨laïnen et al., 2007). Flavonoids also inhibit the production of proinflammatory cytokines and chemokines, including TNF-a, IL-1b and monocyte chemoattractant protein-1 (Sato et al., 1997; Wadsworth and Koop, 1999; Nair et al., 2006; Sharma et al., 2007). These effects are likely mediated through NF-kB, an important regulator of many proinflammatory genes and found to be active in many proinflammatory conditions. In vitro studies using mononuclear cells from pre-eclamptic women have shown that endogenous NF-kB activation and TNF-a and IL-1b release are elevated compared with non-pregnant women and normotensive pregnant women (Giorgi et al., 2012). However, when the cells were treated with a silibinin, a main component of the flavonolignan extract silymarin from milk thistle, levels of NF-kB and cytokines TNF-a and IL-1b were reduced (Giorgi et al., 2012). Although the mechanism by which this extract exerts its anti-inflammatory activity is unknown, in a human intestinal cell line (Caco-2), polyphenols could inhibit NF-kB by preventing its inhibitor, IkB-a, from being deactivated by phosphorylation (Romier et al., 2008). Moreover, Bharrhan et al. (2012) found that polyphenolic compounds down-regulate the levels of p50, a NF-kB subunit, in rat liver nuclear extracts, which would further inhibit downstream signalling of NF-kB. Polyphenols are also able to activate PPARs. PPARs are a group of nuclear receptors activated by many factors, including PGs and leukotrienes. When activated, they act as transcription factors and regulate processes such as cellular differentiation, apoptosis, lipid metabolism, peroxisome proliferation and inflammatory responses. During pregnancy, PPAR signalling is known to regulate trophoblast invasion and differentiation (Schaiff et al., 2000), placentation (Barak et al., 1999) and maternal metabolism (Waite et al., 2000). Aberrant regulation of the PPAR system is associated with complicated pregnancy-related conditions, including PE, IUGR and preterm birth (Wieser et al., 2008). Evidence from animal knockout studies and in vitro work suggests that PPAR activation inhibits the expression of proinflammatory cytokines and directs the differentiation of immune cells towards anti-inflammatory phenotypes (Devchand et al., 1996; Jiang et al., 1998; Martin, 2010). Many dietary polyphenols have been described as direct agonists of

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pregnant and pre-eclamptic women showed that RAGE protein levels are elevated in both the myometrial and omentum vasculature during pregnancy and more so in PE (Cooke et al., 2003). Several plants rich in phenolic compounds, including lowbush blueberry (Vaccinium angustifolium Ait.), have been shown to inhibit the formation of bovine serum albumin-modified AGEs in vitro (Peng et al., 2008; McIntyre et al., 2009; Ferrier et al., 2012). Vaccinium angustifolium has been used as a traditional medicine for millennia and its potent inhibitory effect on AGE formation may help explain why it is an effective natural health product for diabetes treatment in Canada (Martineau et al., 2006). More recently, in vitro studies have shown that extracts from this plant increase trophoblast migration and invasion (Ly et al., 2013, 2014); two important cell functions required for normal placental development and spiral artery remodelling. Furthermore, evidence including that from placental bed biopsies suggests that abnormal trophoblast invasion and spiral artery remodelling play an important role in the

aetiology of PE (Brosens et al., 1972, 1977). Since the mechanism by which the blueberry extract exerts its effects is still unknown, it would be interesting to investigate if AGEs play a role in trophoblast migration and invasion and therefore, determine if the effects seen with the extract are through an AGE-dependent path. Furthermore, other in vitro models using collagen as a substrate have demonstrated that rutin and its metabolites inhibit the formation of AGE biomarkers, including pentosidine and N 1-carboxymethyl-lysine adducts (Cervantes-Laurean et al., 2006). Similarly, in vivo studies using diabetic rat models have reported that oral consumption of green tea extracts and curcumin reduces the formation of AGEs and the cross-linking of collagen (Sajithlal et al., 1998; Babu et al., 2006). Additionally, polyphenols are known inhibitors of AGE-mediated signalling cascades. Studies using murine microglia demonstrated that some plant-derived polyphenols are able to attenuate AGE-induced NO and TNF-a production in a dose-dependent manner (Chandler et al.,


Figure 2 AGE formation and AGE-mediated activation of NF-kB. (1) AGEs are formed non-enzymatically (Maillard reaction) between carbonyl groups of reducing sugars (e.g. glucose) and amino groups of proteins, lipids and nucleic acids. The early and intermediate stages of the Maillard reaction lead to the reversible formation of intermediate products (e.g. Schiff bases and Amadori products), after which classic rearrangement leads to the irreversible generation of AGEs (2) and cross-linking of proteins (3). (4) Receptor for AGE (RAGE) consists of three extracellular domains, a transmembrane helix and a short cytoplasmic tail. Activation of RAGE by AGEs generates ROS through a membrane-associated enzyme, NAPDH oxidase. (5) Increased ROS production stimulates NF-kB translocation into the nucleus and activation of NF-kB-mediated transcription. (6) Soluble RAGE (sRAGE) is an endogenous RAGE antagonist found in human circulation. It is composed of only the extracellular domain of RAGE and is primarily generated through alternative splicing. sRAGE acts as ‘decoy’ by binding RAGE ligands and preventing them from reaching RAGE.

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Potential hazardous effects of polyphenols The beneficial effects of polyphenols, mainly demonstrated in experimental studies, are encouraging. However, prior to initiating human intervention trials there is a need to examine the potential adverse effects of polyphenols during conception and pregnancy. The influence of polyphenol consumption on male and female fertility and sexual development, fetal health and the bioavailability of substrates are summarized in Table IV and will be discussed below.

Fertility and sexual development Oocyte quality is affected by the intrafollicular microenvironment. During normal embryonic development, programmed cell death or apoptosis functions to remove abnormal or redundant cells in preimplantation embryos, contributing to the formation of organs and the embryo itself (Brill et al., 1999). This process does not occur prior to the blastocyst stage in mouse embryos (Byrne et al., 1999). Instead, induction of cell death during oocyte maturation and early embryogenesis leads to developmental injury (Chen and Chan, 2012). In vitro studies suggest that polyphenols may have a negative impact on female reproductive health. For instance, curcumin, the predominant dietary pigment in turmeric, has been shown to promote mouse oocyte apoptosis which leads to a significant reduction in the rate of oocyte maturation, fertilization and in vitro embryonic development (Chen and Chan, 2012). Another study also noted that curcumin induces apoptosis and developmental injury in mouse blastocysts (Chen et al., 2010). Moreover, Chen and Chan (2012) demonstrated using a mouse model that dietary consumption of curcumin decreased the number of implantations and surviving fetuses, decreased fetal weight and increased the number of resorption sites. Similarly, Murphy et al. (2012) reported that parenteral administration of curcumin decreased folliculogenesis and hastened the onset of puberty in female mice. Neonatal treatment with genistein, an isoflavonoid with estrogenic activity from soya products, has been shown to lead to multi-oocyte follicles in mice (Jefferson et al., 2002). These types of follicles are known to have reduced fertility rates during IVF (Iguchi et al., 1990). Overall, these adverse effects are important to consider and justify further investigations to understand the effects of polyphenols on female fertility and sexual development. In males, treatment with curcumin reduced seminal vesicle weights, but did not alter testes weights (Murphy et al., 2012). Other studies suggest that curcumin reduces the motility and viability of human and murine sperm (Rithaporn et al., 2003; Ashok and Meenakshi, 2004) which results in failure of IVF (Naz, 2011). On the contrary, the adverse effect of EGCG on sperm motility is not significant, but this polyphenol has been shown to have cytogenetic effects on mouse spermatozoa in vitro (Kusakabe and Kamiguchi, 2004). Upon injection into oocytes, a significant proportion of spermatozoa treated with EGCG displayed pronuclear arrest, degenerated sperm chromatin mass and structural chromosome aberrations (Kusakabe and Kamiguchi, 2004). Furukawa et al. (2003) proposed that at high concentrations, as used in this study, EGCG is a pro-oxidant and Kusakabe and Kamiguchi (2004) suggested that this leads to the deterioration of sperm plasma membrane. Furthermore, dietary exposure of pregnant dams to genistein resulted in aberrant or delayed spermatogenesis in the seminiferous tubules of male pups (Delclos et al., 2001). In general, the possible adverse


2010). According to Chandler et al. (2010), five compounds/plant extracts were examined and apigenin was found to be the most potent and did not affect cell viability at the concentrations tested. This study did not investigate the mechanism of action; however, the authors hypothesized, based on previous work, that the inhibitory effects are likely mediated by NF-kB. Rasheed et al. (2009) were able to show that EGCG, a green tea polyphenol, inhibits AGE-induced TNF-a production in human chondrocytes partly by preventing the DNA-binding activity of NF-kB. Green tea catechins also attenuate intermittent hypoxiainduced increases in NADPH oxidase and RAGE expression in Sprague–Dawley rats (Burckhardt et al., 2008). NADPH oxidase is a membrane-associated enzyme responsible for the production of superoxide anions in phagocytic and vascular cells. Red grape juice, red wine and pure polyphenols were able to reduce NADPH oxidase subunit expression at the transcriptional and protein level in human neutrophils and mononuclear cells (Da´valos et al., 2009). Similar results were observed in hypertensive rats given red wine polyphenols in their drinking water. Consumption of red wine polyphenols prevented angiotensin II-induced hypertension and endothelial dysfunction in male rats (Sarr et al., 2006). Moreover, a significant inhibitory effect on vascular ROS production and NADPH oxidase expression was seen in the treatment group (Sarr et al., 2006). Interestingly, hypertension and endothelial dysfunction are two phenomena also seen in PE, thus investigating the role of polyphenols in this context may warrant further investigation. Although polyphenols represent an exogenous therapeutic approach to delay AGE- and RAGE-mediated diseases, the body has endogenous mechanisms dedicated to regulating homeostasis of this system. Studies conducted in vivo and in vitro provide evidence that RAGE signalling can be antagonized by soluble RAGE (sRAGE), an endogenous RAGE antagonist generated by either alternative splicing of RAGE mRNA or cleavage of the extracellular domain of RAGE (Stern et al., 2002; Raucci et al., 2008). sRAGE has the same binding specificity as RAGE and may act as a ‘decoy’ by binding RAGE ligands (e.g. AGEs) and preventing them from reaching membrane-bound RAGE, thus inhibiting the intracellular effect. The clinical application of this work was noted by Germanova´ et al. (2010) who reported elevated maternal serum sRAGE levels in the third trimester of women with PE and gestational hypertension. Additionally, Oliver et al. (2011) expanded these findings by demonstrating that maternal serum sRAGE levels were elevated in women with severe PE, but not chronic hypertension, as early as 20 weeks of gestation. This time point is typically recognized as the earliest diagnostic cut-off point for this disease which suggests that in PE, the RAGE system is active at an early gestational age and sRAGE may have a protective function before a patient presents any noticeable clinical symptoms (Oliver et al., 2011). Furthermore, treatment of placental explants with xanthine/xanthine oxidase, an inducer of oxidative stress, stimulated the release of sRAGE; potentially a compensatory mechanism against tissue damage (Oliver et al., 2011). However, higher levels of sRAGE may not be enough to account for the damage induced by the AGE–RAGE system, especially if the levels of RAGE ligands exceed sRAGE scavenging abilities. By measuring the ratio of sRAGE to AGEs, Yu et al. (2012) demonstrated that the sRAGE scavenger capacity is lower in women with Type I diabetes mellitus that subsequently developed PE versus those who did not. In this case, polyphenols may be a useful therapeutic tool to attenuate RAGE activity in disease. Unfortunately, the effects of polyphenols on sRAGE expression during pregnancy are still unknown.

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Table IV Potential harmful effects of polyphenols on reproductive health and early development. Field

Polyphenol

Experimental model

Biological effect

............................................................................................................................................................................................. Fertility and sexual development

Curcumin

Female mice

Male mice

Genistein

EGCG

Murine sperm in vitro

Fetal health

Not specific (estimated total intake .75th percentile)

Prospective analysis in pregnant women

Increase ductal velocities and right-to-left ventricular ratios in exposed fetuses9,18

Bioavailability of nutrients

Red wine and green tea

Caco-2

Increase OC uptake15

Isoxanthohumol, Xanthohumol

BeWo

Reduce thiamine uptake (in chronic treatment)12

Epicatechin, Isoxanthohumol

Reduce folic acid uptake (in acute treatment)13

Quercetin, isoxanthohumol, xanthohumol

Increase folic acid uptake (in chronic treatment)13

Chrysin, EGCG, Quercetin, Resveratrol, Xanthohumol

Reduce glucose uptake (in acute treatment)1

Catechin, Epicatechin, Rutin

Increase glucose uptake (in acute treatment)1

Myricetin, Rutin

Increase glucose uptake (in chronic treatment)1

EGCG, epigallocatechin gallate; OC, organic cation. 1 Arau´jo et al. (2008), 2Ashok and Meenakshi (2004), 3Chavarro et al. (2008), 4Chen et al. (2010), 5Chen and Chan (2012), 6Delclos et al. (2001), 7Dillingham et al. (2005), 8Fraser et al. (2006), 9Galaõ et al. (2010), 10Jacobsen et al. (2014), 11Jefferson et al. (2002), 12Keating et al. (2006), 13Keating et al. (2008), 14Kusakabe and Kamiguchi (2004), 15Monteiro et al. (2005), 16 Murphy et al. (2012), 17Rithaporn et al. (2003), 18Zielinsky et al. (2010).

effects of polyphenols on male reproduction require careful consideration and further investigation, particularly in human studies. Most studies on polyphenols and their effects on fertility and sexual development have used animal models, thus data from human studies is scarce. However, research on isoflavones and fertility in both men and women has been identified in the literature. Isoflavones are phytoestrogens with chemical structures that closely resemble 17-b-estradiol and therefore, have the potential to bind to both membrane and nuclear estrogen receptors, exert estrogenic activity and alter reproductive function (Vitale et al., 2013). A cross-sectional study by Jacobsen et al. (2014) reported that North American Adventist women aged 30–50 years old with high isoflavone intake (≥40 mg/day) had a higher incidence of nulliparity and nulligravidity compared with women with low isoflavone intake (,10 mg/day). Other studies have eased the concerns regarding the potential negative effects of isoflavone consumption on female fertility by reporting that isoflavone intake is not associated with sporadic anovulation (Filiberto et al., 2013) and that higher urinary isoflavone levels may be associated with a shorter time to

pregnancy among couples who are attempting to conceive (Mumford et al., 2014). Contrasting findings are also evident in studies examining the effects of isoflavones on male fertility. For instance, studies report that higher intake of soy foods and soy isoflavones is associated with lower sperm concentration (Chavarro et al., 2008) and decreased serum levels of dihydrotestosterone (Dillingham et al., 2005). However, evidence from other studies suggests that isoflavone intake does not adversely affect semen quality parameters, including sperm concentration and sperm motility and morphology in healthy males (Mitchell et al., 2001; Beaton et al., 2010). Genistein has also been shown to accelerate capacitation and acrosome loss in human and mouse sperm, although human gametes appear to be more sensitive (Fraser et al., 2006). Thus, despite the many reported benefits of polyphenol administration, data highlighting the potential hazards of polyphenols, the variation of results between heterogeneous studies, and the possibility of species-specific susceptibility stresses the need for caution and further study in humans prior to implementing recommendations for clinical practice.


Isoflavones

Human and murine sperm in vitro Female mice Female rats Cross-sectional study in non-pregnant women Male partners in subfertile couples Healthy men (20– 40 years old) Human and murine sperm in vitro

Promote oocyte and blastocyst apoptosis4,5 Decrease number of implantations and surviving fetuses5 Increase number of resorption sites5 No effect on placental weight5 Reduce fetal weight5 Decrease folliculogenesis and hasten the onset of puberty16 Reduce seminal vesicle weight16 No effect on testes weight16 Reduce motility and viability of sperm2,17 Increase number of multi-oocyte follicles11 Alter spermatogenesis in seminiferous tubules of male pups6 Higher incidence of nulliparity and nulligravidity (estimated intake ≥40 mg/day)10 Inverse association between soy food intake and sperm concentration3 Decrease serum levels of dihydrotestosterone7 Accelerate capacitation and acrosome loss (human sperm more sensitive)8 No effect on sperm motility14 Chromosomal abnormalities14

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Fetal health

Bioavailability of substrates Polyphenols are known to target the intestine and therefore, can affect intestinal absorption of nutrients, drugs and other exogenous compounds (i.e. xenobiotics). Similarly, polyphenols that are absorbed from the gastrointestinal system into the maternal circulation can target the placenta and affect placental transport of nutrients and other bioactive substances (Martel et al., 2010). Polyphenols have been reported to affect the bioavailability of various substrates, including organic cations (OCs), thiamine, folic acid (FA) and glucose. OCs possess net charges at physiological pH. Some examples include various drugs (e.g. antihistamines, antacids and antihypertensives), vitamins (e.g. thiamin and riboflavin), amino acids and bioactive amines (e.g. catecholamines, serotonin and histamine) (Zhang et al., 1998). 1-Methyl-4-phenylpyridinium (MPP+) is widely used as a model for OC intestinal uptake studies because it is not metabolized in vivo and is efficiently taken up by intestinal epithelium (Martel et al, 2000; Martel et al., 2010). Red wine has been shown to increase 3H-MPP+ uptake in Caco-2 cells in a dose-dependent manner (Monteiro et al., 2005). In contrast, white wine caused a slight decrease in MPP+ uptake. Since both of these wines had approximately the same amount of ethanol, Monteiro et al. (2005) concluded that the differences in their effects were most likely attributed to non-alcoholic components such as polyphenols. Green tea has also been shown to increase MMP+ uptake in Caco-2 cells more so than black tea, which may be explained by differences in their EGCG content (Monteiro et al., 2005). Thiamine is a complex water-soluble B vitamin (vitamin B1) that is required during pregnancy for normal fetal growth and development. Therefore, understanding the regulation of thiamine transport across the placenta is important. Keating et al. (2006) examined the shortand long-term effects of different phenolics on [3H] thiamine uptake in BeWo cells, a human syncytiotrophoblast cell line. In the short-term study, none of the 10 compounds tested influenced thiamine transport. Long-term treatment with the prenylated chalcones xanthohumol or isoxanthohumol, which are commonly found in beer, significantly reduced thiamine uptake by BeWo cells. This effect was not mediated through differential mRNA expression of the thiamine transporters, ThTr-1 and ThTr-2, or the human serotonin transporter, both of which have been previously reported to be involved in thiamine uptake in BeWo cells

Dietary intake of polyphenols during pregnancy Polyphenol consumption varies greatly between individuals and cultures. An epidemiological study in southern Germany reported that the average phenolic acid intake of men and women was 222 mg/day within a large range from as low as 5 to 983 mg/day (Radtke et al., 1998). Individuals who drink more than two cups of coffee per day can easily consume 0.5– 1 g of phenolic acids per day, as a 200 ml cup of


Maternal intake of polyphenol-rich foods and beverages during the third trimester has been associated with fetal ductal constriction (Zielinsky et al., 2010), a risk factor for neonatal pulmonary hypertension (Levin et al., 1979). In a prospective study conducted by Zielinsky et al. (2010), measurements of fetal ductal flow dynamics were compared between fetuses exposed to high levels of polyphenols (i.e. estimated daily maternal consumption above 1089 mg) and low levels of polyphenols (i.e. unexposed fetuses; estimated daily maternal consumption below 127 mg). Results indicated that fetuses exposed to polyphenolrich foods had higher ductal velocities and right-to-left ventricular ratios than unexposed fetuses; however, these parameters were still within the normal range (Galaõ et al., 2010). Although maternal restriction of polyphenol-rich foods was reported to reverse the effect on ductal constriction (Zielinsky et al., 2012), whether this finding warrants changes in perinatal diet remains to be determined, but certainly should be thoroughly investigated before recommendations are made.

(Keating et al., 2006). To further elucidate the mechanism by which this effect occurs, future studies should examine the protein levels of these transporters following treatment and quantify other transporters known to carry thiamine across the placenta (e.g. amphiphilic solute facilitator family). FA is a member of the large family of B vitamins and its derivatives are required for a variety of cellular functions, including nucleic acid synthesis and amino acid metabolism (Martel et al., 2010). Folate is the naturally occurring form of the vitamin and is especially important during pregnancy for preventing fetal neural tube defects (Lucock, 2000). One Japanese study noted that circulating levels of folate appear to be lower in healthy pregnant women who consume high levels (i.e. greater than the 75th percentile of participants) of green or oolong tea compared with healthy pregnant women who do not consume high levels of these beverages (Shiraishi et al., 2010). However, recent data from Colapinto et al. (2011) showed that the vast majority of Canadian women in child bearing age are receiving excessively high levels of folate through supplementation and food. Therefore, folate deficiency does not seem to be an issue in Canada. In vitro studies using BeWo cells have shown that acute treatment with the polyphenols epicatechin or isoxanthohumol reduced FA uptake (Keating et al., 2008). Conversely, xanthohumol, quercetin or lower concentrations of isoxanthohumol increased FA uptake (Keating et al., 2008). Polyphenols are believed to affect FA transport in BeWo cells through direct interaction with FA transporters rather than influencing transporter expression (Keating et al., 2008). Since the BeWo cell line only acts as a simple model for a more complex biological system, caution should be taken when interpreting these results. For instance, the apparent differences in acute and chronic exposure of polyphenols in vitro may not necessarily be reflective of what is seen in vivo, thus further studies using villous explants or animal models would be interesting to pursue. Glucose is the main energy substrate for metabolism and growth of the feto-placental unit (Martel et al., 2010). Since the fetus cannot synthesize the amount of glucose required for optimal development, it must obtain glucose from the maternal circulation. Therefore, placental transport of glucose is a major determinant of fetal health. Glucose transport is mediated by members of the GLUT family of transporters; GLUT1 being the predominant transporter in the placenta (Barros et al., 1995; Hahn et al., 1995). Short-term treatment of BeWo cells with resveratrol, EGCG, quercetin, chrysin and xanthohumol reduced glucose uptake while rutin, catechin and epicatechin increased glucose uptake in these cells (Arau´jo et al., 2008). Chronic treatment with rutin and myricetin increased glucose uptake in this model. However, whether polyphenols when taken together with other phenolics or whole foods have similar effects in humans is still unknown.

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Human studies and translational potential The increasing interest and public awareness surrounding the potential health benefits of polyphenol consumption, as well as the widespread

availability and accessibility of polyphenols through the use of nutritional supplements and fortified foods, has prompted extensive research focused on the biological effects of these compounds in regards to chronic disease prevention and health maintenance. However, these studies have included mostly cell and animal data, with minimal human investigations. In fact, much less human data are available on the effects of polyphenol consumption during pregnancy. Nordeng and Havnen (2005) interviewed a total of 400 post-partum women in Norway and found that 36% of the women reported herbal medicine use during their pregnancy. Moreover, both women who had used herbal medicines during pregnancy and those who did not, had a positive attitude towards the consumption of polyphenol-rich supplements (Nordeng and Havnen, 2005). In a different study conducted in Italy, 700 pregnant women were interviewed and 27% of these women reported that they consumed herbal supplements every day for at least 3 months (Facchinetti et al., 2012). Similar findings have been documented in a more recent multinational study in which nearly 30% of the 9500 women interviewed reported the use of herbal medicines (Kennedy et al., 2013). Overall, the use of supplements rich in polyphenols appears to be relatively high, thus identifying the herbal products used by pregnant women and understanding the potential benefits or harm is needed. In chronic diseases, including cancer, cardiovascular disease and diabetes, the consumption of polyphenol-rich foods and beverages has been reported to have antioxidant and anti-inflammatory effects, such as increasing the plasma antioxidant capacity in humans (Prior et al., 2007) and decreasing the incidence of chronic inflammatory diseases in many subpopulations (Yoon and Baek, 2005). To our knowledge, there have been no studies to date examining the relationship between polyphenols and the incidence of pregnancy-related complications associated with oxidative stress and inflammation. However, Facchinetti et al. (2012) reported that women who consumed almond oil, a herbal supplement rich in polyphenols (Mandalari et al., 2010), on a regular basis had a higher incidence of preterm birth. Most of the human studies related to polyphenols and reproductive health focus on the effects of isoflavone consumption on male and female fertility, and there appears to be no clear consensus in this field (Mitchell et al., 2001; Dillingham et al., 2005; Chavarro et al., 2008; Beaton et al., 2010; Filiberto et al., 2013; Jacobsen et al., 2014; Mumford et al., 2014). Other studies have reported that maternal intake of polyphenol-rich foods and beverages during pregnancy may have adverse effects on fetal health (Zielinsky et al., 2010, 2012); however, this topic is also controversial and remains to be reconciled in the current literature. Overall, studies examining the biological effects of polyphenol consumption on human reproductive health are limited and inconclusive. Based on the evidence accumulated from in vitro studies and animal models, as well as human studies in other contexts, some may initially believe that polyphenols have potential health benefits on human reproduction. On the other hand, investigators who have studied the effects of polyphenols on fertility, sexual development and fetal health, have highlighted significant health concerns that should be considered prior to conducting clinical trials and implementing recommendations for clinical practice. The findings from these animal studies are difficult to extrapolate to humans due to a variety of species-related differences, including inter- and intra-species variation in digestion, absorption, and metabolism of polyphenols, and concentration and composition of the experimental treatment. Therefore, further studies in humans are required


coffee contains 20– 675 mg of the phenolic acid chlorogenic acid (Clifford, 2000a, b). The estimated mean flavonoid intake for men and women (non-pregnant) in the USA, captured through the nationally representative National Health and Nutrition and Exercise Examination Survey (NHANES), is roughly 190 mg/day (Chun et al., 2007); however, the average polyphenol intake obtained from one 24 h recall may be an underestimate. As the use of nutritional supplements continues to grow in popularity, the concentration of polyphenols found within these capsules and powders should be considered when determining total phenolic intake. Individuals who take supplements are estimated to consume 100 times more polyphenols than the common intakes in a Western diet (Mennen et al., 2005), highlighting the importance of monitoring the source of polyphenol ingestion. To assess the possible beneficial and harmful effects of polyphenols, validated methods are being developed to quantify the concentration of these compounds in dietary supplements (Harris et al., 2007; Colson et al., 2010; Hicks et al., 2012) and food sources. However, adequately powered studies with large sample sizes are needed to properly correlate polyphenol intake and health outcome. The use of biochemical markers to measure polyphenol intake during pregnancy is subject to interpretation errors caused by individual differences in absorption and metabolism, genetics and metabolic changes during pregnancy. Food frequency questionnaires (FFQ) have well-documented limitations, but are the most common method used to evaluate dietary intake patterns given the low cost and ease of administration (Archer et al., 2013; Schoeller et al., 2013). A recent study conducted by Vian et al. (2013) was the first to test the reproducibility and validity of a FFQ to quantify total ingestion of polyphenols for 120 pregnant women in Brazil. The average daily intake of total polyphenols estimated by the FFQ was roughly 1 g, and this FFQ showed high reproducibility and validity for the quantification of total polyphenol consumption. Studies that provide more precise individual data concerning intake of specific classes of polyphenols during pregnancy are required and will further our understanding of their potential impact on reproductive health. Similarly, continuing to expand on food composition data through the use of publicly accessible and open access databases, such as ‘Phenol-Explorer’, will provide comprehensive data on polyphenol content in foods and therefore, assist with identifying potential hazards of consuming excess polyphenol-rich foods. Although the current methods for measuring polyphenol content in foods and dietary supplements (e.g. oxygen radical absorbance capacity assay and Folin – Ciocalteu method) is accurate (Prior et al., 2005), developing a single standardized assay would be beneficial to compare foods or nutritional supplements. Lastly, obtaining accurate information with regards to maternal consumption of nutritional supplements high in polyphenols, such as ginger, cranberry and raspberry herbal medicines (Kennedy et al., 2013), will be useful for risk assessment and help guide clinical and research efforts. As these studies are in their infancy, considerably more research effort is needed in this area.

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and should employ large cohorts, with adequate power and sample sizes to detect changes in the primary outcome.

Conclusion and recommendations for future research

Acknowledgements The authors thank Dr Tony Durst and Dr Ammar Saleem for their comments on the figures.

Authors’ roles C.L., J.Y.L., Z.M.F., J.T.A., J.F. and A.G. made substantial contributions to the conception and design of the manuscript. C.L., Z.M.F., J.T.A, J.F. and A.G. were involved in the acquisition of data. C.L., J.Y.L., Z.M.F., J.T.A., J.F. and A.G. played a role in the analysis and interpretation of data. C.L. drafted the manuscript and J.Y.L., Z.M.F., J.T.A., J.F. and A.G. critically revised the manuscript. C.L., J.Y.L., Z.M.F., J.T.A., J.F. and A.G. contributed to the final approval of the version to be published.

Funding The following funds were used to support the authors during the preparation of the manuscript: Queen Elizabeth II Graduate Scholarship in

Conflict of interest The authors declared no conflict of interests.

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Both positive and negative effects have been associated with the consumption of polyphenol-rich foods and beverages in human studies, as well as with the treatment of individual phenolic compounds in experimental in vitro and in vivo models. The mechanisms responsible for these effects have only recently started to be elucidated, especially in the context of reproductive health and pregnancy. As such, we must remain critical particularly for at-risk populations, such as pregnant women, when drawing conclusions regarding the potential health benefits or adverse effects of polyphenols. Successful advancement in this field of research will require the development of extensive food composition tables for polyphenols and standardized methods for executing experimental procedures. This will allow researchers to conduct thorough observational epidemiological studies and grant confidence when comparing results in the literature. Since the active compound responsible for the biological effect may not be the native polyphenol found in food, further studies are required to characterize the activity of the metabolites rather than simply the native compounds which are currently the most often tested agents in in vitro studies. Finally, identifying the normal physiological range of polyphenols and their metabolites in adult tissues and fetal tissues is of utmost importance if scientists aim to determine if the effects achieved from a certain dose in an experimental study are physiologically relevant. Determining the clinical relevance of results obtained from animal and in vitro studies is difficult as these studies are conducted at doses which may exceed normal physiologic concentrations. Even if concentrations are deemed ‘low’ in the fetus, we cannot disregard their potential biological activities as the effective concentration in the fetus might be much lower than in an adult. Collectively, all of these aspects must be considered in the design of future experimental studies, irrespective of whether they are aimed at evaluating beneficial or adverse effects of polyphenols.

Science and Technology (C.L.); Department of Cellular and Molecular Medicine, University of Ottawa (C.L.); Division of Maternal-Fetal Medicine, The Ottawa Hospital (Z.M.F., A.G.); Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship (Z.M.F.); Mitacs Elevate Postdoctoral Fellowship (J.F.); Natural Sciences and Engineering Research Council Discovery Grant (J.T.A.); The Ottawa Hospital Academic Medical Organization (J.Y.L., A.G.).

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A Mouse Model for Studying Nutritional Programming: Effects of Early Life Exposure to Soy Isoflavones on Bone and Reproductive Health.

Examining negative effects of early life experiences on reproductive and sexual health among female sex workers in Tijuana, Mexico.

Role of dietary polyphenols in the management of peptic ulcer.

Early lung development: lifelong effect on respiratory health and disease.

Effects of early life stress on amygdala and striatal development.

New Insights on the Use of Dietary Polyphenols or Probiotics for the Management of Arterial Hypertension.

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The role of dietary polyphenols in the moderation of the inflammatory response in early stage colorectal cancer.

Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties.

Dietary polyphenols in prevention and treatment of prostate cancer.

The effects of an anabolic steroid (oxandrolone) on reproductive development in the male rat.