Rev Endocr Metab Disord DOI 10.1007/s11154-016-9326-7
Polycystic ovary syndrome (PCOS) and endocrine disrupting chemicals (EDCs) Eleni Palioura 1 & Evanthia Diamanti-Kandarakis 1
# Springer Science+Business Media New York 2016
Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of unclear etiopathogenesis that is likely to involve genetic and environmental components synergistically contributing to its phenotypic expression. Endocrine disrupting chemicals (EDCs) and in particular Bisphenol A (BPA) represent a group of widespread pollutants intensively investigated as possible environmental contributors to PCOS pathogenesis. Substantial evidence from in vitro and animal studies incriminates endocrine disruptors in the induction of reproductive and metabolic aberrations resembling PCOS characteristics. In humans, elevated BPA concentrations are observed in adolescents and adult PCOS women compared to reproductively healthy ones and are positively correlated with hyperandrogenemia, implying a potential role of the chemical in PCOS pathophysiology, although a causal interference cannot yet be established. It is plausible that developmental exposure to specific EDCs could permanently alter neuroendocrine, reproductive and metabolic regulation favoring PCOS development in genetically predisposed individuals or it could accelerate and/or exacerbate the natural course of the syndrome throughout life cycle exposure.
Keywords Endocrine disrupting chemicals . Bisphenol A . PCOS . Reproduction . Metabolism
* Evanthia Diamanti-Kandarakis [email protected]
1
Department of Endocrinology and Center of Excellence in Diabetes, Euroclinic Athens, Athens, Greece
1 Introduction Polycystic ovary syndrome (PCOS) is a mutlifactorial endocrinopathy of unknown etiology affecting approximately 5–10 % of women in the reproductive age spectrum [1–4]. Cardinal features of the syndrome are reproductive and metabolic aberrations central to which is abnormal gonadotropin secretion, disrupted ovarian follicular maturation and steroid hormones secretion as well as disturbed insulin action leading to insulin resistance and compensatory hyperinsulinemia [5, 6]. The pathogenesis of PCOS is believed to involve the interaction of genetic and environmental components synergistically contributing to the final phenotypic expression [7–9]. The role of environmental factors is under intensive investigation especially with regard to obesity and dietary habits that are proved to deteriorate PCOS symptoms [8, 10]. It has been hypothesized that the environment secondarily interacts with genes to define the clinical phenotype in a primary, genetically determined, hyperandrogenic ovarian defect [11]. The role of the environment in PCOS pathogenesis has recently expanded to include a broad category of industrial chemicals that are widespread distributed in the atmosphere and have the potency to interfere with all hormone-sensitivity systems [12]. These agents known as endocrine disrupting chemicals (EDCs) can interact with several stages of natural blood-borne hormones metabolism from their initial synthesis and secretion to their elimination and therefore can modify several biological processes [13]. They are incriminated to disrupt endocrine regulation of metabolism and reproduction through multiple modes of action beyond the traditional estrogen/androgen receptors mediated pathways [12]. With respect to PCOS the role of environmental chemicals is under investigation given that animal models of prenatal androgenization show pathophysiological changes that result in fetal programming of PCOS traits [14, 15]. It is plausible
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that exposure to environmental chemicals during sensitive stages of development could provoke deregulation of the reproductive system leading to PCOS-resembling abnormalities after puberty. Up to date, the majority of published literature concerning EDCs and PCOS is focused on the role of Bisphenol A (BPA) a ubiquitous chemical widely used in the manufacture of polycarbonate plastics and epoxy resins [16]. Therefore, the following sections of the current review will analyze data linking exposure to endocrine disruptors and in particular BPA with the development of reproductive and metabolic diseases that imitate PCOS characteristics. Finally, human data will be presented with possible mechanisms of interference with PCOS pathogenesis. Future considerations will be finally discussed.
2 Endocrine disruptor’s effects on the female reproductive system-a link to PCOS There has been extensive evidence from experimental studies showing that exposure to endocrine disruptors results in impaired ovarian physiology leading to morphological and functional alterations of the female reproductive system [17]. In fact, environmental pollutants are shown to interfere with several aspects of follicle growth and ovarian steroid hormone production [18–20] by modifying the expression and/or activity of regulatory enzymes [21] or by altering hormone receptor binding and action [19]. Furthermore, early exposure to EDCs has also been experimentally linked to reproductive tract malformations [22], earlier pubertal timing [23], alterations of the hypothalamic-pituitary-ovarian axis [24], disorders of ovulation [25], fertility and fecundity [26] and development of PCOS traits. In humans, a role of EDCs has been implied in the pathogenesis of several female reproductive disorders, including precocious puberty, endometriosis, female infertility, premature ovarian failure, PCOS [12] though a causal interference has not yet been established. The potential involvement of EDCs on PCOS pathogenesis is implied by animal studies of early life exposure showing the development of a PCOS like syndrome later at adult life [27]. Bisphenol A (BPA) is the most common environmental pollutant incriminated for reproductive and metabolic disorders resembling PCOS in rodents and most published literature concerning EDC and PCOS is limited to this estrogenic chemical. BPA is a ubiquitous contaminant with a broad spectrum of applications used primarily in the manufacture of polycarbonate plastic and epoxy resin [28, 29]. Due to its estrogenic properties, there is increasing concern relative to its adverse effects on normal differentiation and function of the female reproductive system. Studies of laboratory animals document BPA detrimental effects on neuroendocrine regulation of reproduction and on the ovary per se. Acceleration of puberty onset
(indicated by early vaginal opening) has been reported in rodents intrauterine exposed to environmentally relevant BPA levels [30, 31]. Changes of the HypothalamicPituitary-Ovarian axis (HPO) axis have also been reported either as interruption of gonadotrophin secretion (lower luteinizing hormone levels) [32] or as interruption of hypothalamic Gonadotropin-Releasing hormone release [33]. Moreover, developmental exposure to BPA has been related with adverse effects on several aspects of ovarian physiology from the early stage of oogenesis to oocyte maturation and fertilization [34]. A considerable number of in vitro and animal studies indicate that developmental BPA exposure disrupts oogenesis and early meiosis [35–37] as well as normal follicle growth leading to accelerated follicle transition and increased incidence of atretic follicles [38, 39]. Furthermore, ovarian steroidogenesis is also affected with increased [21, 27] or decreased androgen/estradiol levels [40] following BPA administration. Interestingly, these alterations are associated with BPA induced modifications of ovarian steroidogenic enzymes including 17β hydroxylase (P450c17), cholesterol side chain cleavage enzyme (P450scc) and steroidogenic acute regulatory protein (StAR) [21] some of which are also implicated in PCOS hyperandrogenism [41]. Taken together, the data suggest that BPA has the potency/potential to disturb reproductive function either directly at the level of the ovary by affecting follicle maturation and ovarian steroid hormone production or indirectly at the level of the hypothalamic–pituitary unit. Combined with the fact that all these processes are disturbed in PCOS, it could be assumed that BPA may act as an additional, exogenous factor to deteriorate the reproductive phenotype of the syndrome. Suggestive of this hypothesis is a study by Fernandez et al. [27] who investigated the effects of early life BPA exposure on reproductive parameters in a rat animal model. When female Sprague–Dawley rats neonatally (first 10 days postpartum) exposed to the chemical reached adulthood, they exhibited a PCOS-like syndrome characterized by biochemical hyperandrogenemia (elevated testosterone levels), unovulation, infertility, polycystic ovarian morphology and increased GnRH pulse frequency. The severity of the effects was dose-dependent with the highest dose (500 μg/50 μL) causing the full clinical phenotype due to modifications of the hypothalamic–pituitary–gonadal axis and the environmentally relevant dose (50 μg/ 50 μL) provoking subtle alterations. This animal model clearly demonstrates the development of a PCOS resembling syndrome following early life BPA exposure. This fits with the hypothesis that exposure to endocrine disrupting chemicals during sensitive developmental stages could lead to irreversible changes in endocrine systems that become evident later in adult life.
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3 Endocrine disruptor’s effects on metabolism-a link to PCOS PCOS has been typically associated with a broad spectrum of metabolic disorders and consequences including obesity, insulin resistance and compensatory hyperinsulinemia, impaired glucose metabolism and type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, hypertension, nonalcoholic fatty liver disease and high risk of cardiovascular disease [42, 43]. Metabolic aberrations co-exist and further exacerbate the reproductive features of PCOS creating a vicious cycle in which insulin resistance poses a central role [44]. There is considerable experimental evidence linking endocrine disrupting chemicals with metabolic alterations through deregulation of normal lipid and glucose homeostasis. Importantly, the world’s modern epidemics -obesity and diabetesare believed to be partly related to the increasing presence of such substances in the atmosphere [45, 46]. The so called Bobesogens^ are environmental chemicals presumed to favor obesity development through inappropriate regulation of energy and lipid metabolism [47, 48]. Many of their effects are mediated through the peroxisome proliferator-activated receptor- γ (PPAR- γ) who acts as a regulator of adipocyte differentiation [48]. Furthermore, the presence of Bdiabetogenic^ pollutants could partly explain the increasing incidence of metabolic diseases such as the metabolic syndrome and diabetes [49]. Metabolic effects may represent an indirect pathway which in combination with reproductive abnormalities favors the development of a PCOS phenotype in genetically predisposed individuals. BPA is a characteristic example of such interaction as it has been incriminated for multiple disorders including metabolic ones. Remarkably, epidemiological evidence link BPA detected in urine with cardiovascular disease, type 2 diabetes and liver enzyme abnormalities in a representative sample of adult US population [50]. Animal models of prenatal [31] and perinatal [51, 52] BPA exposure demonstrate a disruption of weight control mechanisms leading to increased adipose storage in early postnatal and adult life. These obesogenic effects may be mediated by up-regulation of adipogenesis-associated genes [52] triggering adipocyte differentiation as shown in a culture of human adipose stromal/stem cells [53]. Similarly, in vitro studies of 3T3-L1 cells highlight BPA potency to stimulate lipid accumulation in target cells involved in the metabolic syndrome [54] and to accelerate their conversion to adipocytes through the phosphatidylinositol 3-kinase pathway [55]. Furthermore, BPA is shown to control lipid homeostasis through alteration of adipokine secretion from human adipose tissue. To be more specific, in human adipose depots BPA stimulates the release of cytokines favoring adiposity and insulin resistance namely Interleukin-6 (IL-6) and Tumor Necrosis Factor α (TNF-α) [56] whereas it inhibits the release of adiponectin that protects against metabolic syndrome [57].
BPA is also associated with deregulation of glucose homeostasis through profound effects to pancreatic cells even at environmentally relevant doses [58, 59]. With respect to β-pancreatic cells function, BPA is shown in vivo to rapidly increase insulin and decrease glucose levels while in a state of prolonged exposure BPA leads to chronic hypersecretion of insulin followed by insulin resistance [58]. In a-pancreatic cells, BPA is shown to suppress glucagon secretion by inhibiting the intracellular calcium ion oscillatory pattern in the absence of glucose [59]. In experimental models, perinatal and gestational exposure to BPA is related to impaired glucose tolerance and increased insulin resistance in male adult offspring [58] while increased body weight, adiposity and lipids abnormalities have also been reported [60, 61]. It seems biological plausible that developmental exposure to BPA may disrupt glucose and lipid homeostasis, possibly contributing to the future development of metabolic syndrome, a condition commonly presented in PCOS patients. Recent data suggest that early life BPA exposure can modify the expression of metabolic genes involved in hepatic lipogenesis at weaning [52] and favor steatosis development in male adult animals [62] by epigenetic reprogramming of hepatic fatty acid β-oxidation [63]. Liver steatosis, recognized as the hepatic manifestation of metabolic syndrome, is a frequent finding in PCOS women [64]. Taken together, the above data demonstrate BPA potency to inappropriately influence adipogenesis and fat storage, to disrupt normal pancreatic cells function and favor the development of steatosis.
4 Endocrine disruptors and PCOS: human data The first study to determine serum BPA concentrations in humans was conducted by Takeuchi and colleagues more than a decade ago [65]. In this investigation, researchers measured and compared the levels of the chemical in a small-sized group of PCOS patients, a group of reproductively healthy women and a group of healthy men. BPA levels presented a gender differentiation as significantly elevated chemical levels were reported in normal men compared to normal women and in women with polycystic ovary syndrome compared to control females. Furthermore, a positive correlation was observed between BPA levels and serum total and free testosterone concentrations in all subjects implying a potential role of hyperandrogenemia on chemical’s metabolism [65]. A subsequent study of the same research group oriented to women with ovarian dysfunction included obese and nonobese PCOS women and same- weight healthy female individuals. Measurements revealed significantly increased serum BPA levels in both non-obese and obese PCOS women compared to the subgroup of non-obese control participants while they remained unchanged compared to obese controls [66]. Similarly, in this study, BPA levels were positively correlated
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Fig. 1 Possible mechanisms of Bisphenol A interaction with androgens. BPA may enhance androgen production in ovarian theca cells and may modulate their hepatic metabolism by interacting with SHBG and with enzymes regulating their hydroxylation. Furthermore, BPA and its metabolites act as androgen and progesterone receptors ligands, potentially inhibiting the endogenous native hormones. Finally,
androgens per se could down-regulate BPA liver catabolism increasing its circulating levels. AR receptors Androgen Receptors, BPA Bishpenol A, PR receptors Progesteron Receptors, SHBG Sex Hormone-Binding Globulin, UDP glucuronosyl transferase uridine diphosphate– glucuronosyl transferase
with androgens (total and free testosterone, androstenedione, dehydroepiandrosterone sulfate) and for the first time a relationship was demonstrated between BPA levels and body mass index (BMI) [66]. However, in a larger subsequent study of 71 PCOS and 100 healthy women stratified by BMI, Kandaraki et al. [67] showed that bisphenol A levels are higher in PCOS women compared to controls, independently of body weight as both lean and overweight PCOS individuals had elevated BPA levels compared to normal ovulating nonhyperandrogenemic women of matched body weight. Statistical analysis again revealed a positive correlation between BPA levels with serum testosterone (r = 0.192, P < 0.05) and androstenedione levels (r = 0.257, P < 0.05) while a positive correlation was demonstrated between BPA and the Matsuda index (r = 0.273, P < 0.05) that estimates insulin resistance. In another study of premenopausal women with PCOS, there was a positive association between BPA levels with hepatosteatosis and markers of low-grade inflammation including spleen enlargement [68]. A recent cross-sectional study contacted among female workers from BPA-exposed and unexposed factories in China, added to the evidences that BPA has a deleterious impact on human reproductive health and women’s hormone homeostasis showing that there was a significant positive association between increased urine BPA concentration and higher prolactin and progesterone levels [69]. All the above studies were conducted in adult PCOS women. Interestingly, in a group of PCOS adolescents, similar
effects were observed as elevated BPA levels were documented in PCOS adolescents compared to controls independent of obesity [70]. Similarly, BPA was strongly correlated with androgens, however, the interplay between these parameters is not yet clear, although it seems bidirectional. In vivo and in vitro data are pointing that BPA exerts its endocrine disruption activity through agonistic and antagonistic interference with the steroidal pathways of the female reproductive system.
Fig. 2 The potential pathophysiological mechanisms involved in Bisphenol A interference with PCOS pathogenesis. BPA interacts with genetic factors favoring the development of neuroendocrine, reproductive and metabolic aberrations resembling PCOS characteristics
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Multiple pathways can be affected by these interferences including binding to steroid receptors and steroid binding proteins or modulating steroidogenic enzymes in the female reproductive tissues. One hypothesis suggests that BPA directly stimulates ovarian theca cells to secrete androgens through upregulation of steroidogenic enzymes expression including 17β hydroxylase (P450c17), cholesterol side chain cleavage enzyme (P450scc) and steroidogenic acute regulatory protein (StAR) [21]. Furthermore, BPA could indirectly increase androgens by modifying their metabolism at the level of the liver through two mechanisms. The first mechanism involves interaction between BPA and sex hormone-binding globulin (SHBG) that could displace androgens and disturb androgen/estrogen balance leading to increased levels of circulating androgens [71]. The second mechanism possibly involves BPA-induced down-regulation of androgens metabolism/ hydroxylation by a decrease in testosterone 2ahydroxylase and testosterone 6b-hydroxylase activities which are the enzymes responsible for this process [72]. On the other hand, androgens per se could affect BPA metabolism by down-regulating the activity of uridine diphosphate– glucuronosyl transferase (UDP-glucuronosyltransferase, UGT) the enzyme catalyzing BPA glucuronidation by liver microsomes [73]. Recently, it has been demonstrated that structural binding of BPA, and its 1000 times more potent metabolite 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1- ene (MBP), with Androgen Receptor (AR) and Progesterone Receptor (PR), potentially inhibit the endogenous native AR and PR ligands binding and therefore resulting in target tissue dysfunction [74]. The endocrine disruption activity of BPA can occur through multiple pathways. All mechanisms possibly involved in BPA interaction with androgens are presented in Fig. 1.
The exact mechanisms linking endocrine disrupting chemicals and in particular BPA with PCOS development are yet not fully understood, making future experimental studies critical to determine the molecular basis for the observed reproductive and metabolic alterations in response to BPA as well as to determine how these effects could influence future generations through epigenetic mechanisms. It is important to bear in mind that these studies have some significant parameters to consider in their experimental design. Firstly, the dose of exposure should be relevant to humans given that several studies use toxic levels far above the environmentally equivalent ones. Secondly, exposure to a mixture of endocrine disruptors with additive or synergistic or even antagonistic effects is more likely to occur in humans rather than exposure to a sole contaminant. Thirdly, time of exposure is critical given that early life exposure could permanently alter reproductive and metabolic regulation favoring PCOS development later in adult life, while postnatal exposure could modify PCOS phenotypic expression by exacerbating its symptoms. Above all, it should always be remembered that extrapolation of data obtained from animal studies to humans has the major obstacle of species differences to overcome. It is now accepted that the natural history of PCOS could be modified by interaction with factors such as obesity and diet. Chemicals with endocrine disrupting properties and in particular BPA may represent an additional aggravating factor. Large prospective epidemiological studies using validated biomarkers of BPA exposure need to be undertaken in order to make firm conclusions about the negative impact of BPA on PCOS women. Parallel to that, laboratory studies should reveal all the molecular mechanisms underlying such a relationship. Compliance with ethical standards
5 Concluding remarks Substantial evidence from in vitro and animal studies incriminates endocrine disrupting chemicals and in particular BPA in the induction of reproductive and metabolic aberrations resembling PCOS features. All hormone-sensitive tissues implicated in reproduction such as the hypothalamic–pituitary unit and the ovary per se and in metabolism such as the adipose tissue and pancreas are experimentally deregulated by BPA (Fig. 2). Many of these effects are observed after exposure during sensitive stages of development such as fetal or neonatal life and become obvious when exposed animals reach maturity. In humans, literature is relatively limited to the documentation of elevated BPA levels in adolescents and adults with PCOS compared to healthy individuals which are positively correlated to androgen levels, implying a potential role of BPA in PCOS pathophysiology.
Conflict of interest The authors declare that they have no conflict of interest.
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Polycystic ovary syndrome (PCOS) and endocrine disrupting chemicals (EDCs) Eleni Palioura 1 & Evanthia Diamanti-Kandarakis 1
# Springer Science+Business Media New York 2016
Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of unclear etiopathogenesis that is likely to involve genetic and environmental components synergistically contributing to its phenotypic expression. Endocrine disrupting chemicals (EDCs) and in particular Bisphenol A (BPA) represent a group of widespread pollutants intensively investigated as possible environmental contributors to PCOS pathogenesis. Substantial evidence from in vitro and animal studies incriminates endocrine disruptors in the induction of reproductive and metabolic aberrations resembling PCOS characteristics. In humans, elevated BPA concentrations are observed in adolescents and adult PCOS women compared to reproductively healthy ones and are positively correlated with hyperandrogenemia, implying a potential role of the chemical in PCOS pathophysiology, although a causal interference cannot yet be established. It is plausible that developmental exposure to specific EDCs could permanently alter neuroendocrine, reproductive and metabolic regulation favoring PCOS development in genetically predisposed individuals or it could accelerate and/or exacerbate the natural course of the syndrome throughout life cycle exposure.
Keywords Endocrine disrupting chemicals . Bisphenol A . PCOS . Reproduction . Metabolism
* Evanthia Diamanti-Kandarakis [email protected]
1
Department of Endocrinology and Center of Excellence in Diabetes, Euroclinic Athens, Athens, Greece
1 Introduction Polycystic ovary syndrome (PCOS) is a mutlifactorial endocrinopathy of unknown etiology affecting approximately 5–10 % of women in the reproductive age spectrum [1–4]. Cardinal features of the syndrome are reproductive and metabolic aberrations central to which is abnormal gonadotropin secretion, disrupted ovarian follicular maturation and steroid hormones secretion as well as disturbed insulin action leading to insulin resistance and compensatory hyperinsulinemia [5, 6]. The pathogenesis of PCOS is believed to involve the interaction of genetic and environmental components synergistically contributing to the final phenotypic expression [7–9]. The role of environmental factors is under intensive investigation especially with regard to obesity and dietary habits that are proved to deteriorate PCOS symptoms [8, 10]. It has been hypothesized that the environment secondarily interacts with genes to define the clinical phenotype in a primary, genetically determined, hyperandrogenic ovarian defect [11]. The role of the environment in PCOS pathogenesis has recently expanded to include a broad category of industrial chemicals that are widespread distributed in the atmosphere and have the potency to interfere with all hormone-sensitivity systems [12]. These agents known as endocrine disrupting chemicals (EDCs) can interact with several stages of natural blood-borne hormones metabolism from their initial synthesis and secretion to their elimination and therefore can modify several biological processes [13]. They are incriminated to disrupt endocrine regulation of metabolism and reproduction through multiple modes of action beyond the traditional estrogen/androgen receptors mediated pathways [12]. With respect to PCOS the role of environmental chemicals is under investigation given that animal models of prenatal androgenization show pathophysiological changes that result in fetal programming of PCOS traits [14, 15]. It is plausible
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that exposure to environmental chemicals during sensitive stages of development could provoke deregulation of the reproductive system leading to PCOS-resembling abnormalities after puberty. Up to date, the majority of published literature concerning EDCs and PCOS is focused on the role of Bisphenol A (BPA) a ubiquitous chemical widely used in the manufacture of polycarbonate plastics and epoxy resins [16]. Therefore, the following sections of the current review will analyze data linking exposure to endocrine disruptors and in particular BPA with the development of reproductive and metabolic diseases that imitate PCOS characteristics. Finally, human data will be presented with possible mechanisms of interference with PCOS pathogenesis. Future considerations will be finally discussed.
2 Endocrine disruptor’s effects on the female reproductive system-a link to PCOS There has been extensive evidence from experimental studies showing that exposure to endocrine disruptors results in impaired ovarian physiology leading to morphological and functional alterations of the female reproductive system [17]. In fact, environmental pollutants are shown to interfere with several aspects of follicle growth and ovarian steroid hormone production [18–20] by modifying the expression and/or activity of regulatory enzymes [21] or by altering hormone receptor binding and action [19]. Furthermore, early exposure to EDCs has also been experimentally linked to reproductive tract malformations [22], earlier pubertal timing [23], alterations of the hypothalamic-pituitary-ovarian axis [24], disorders of ovulation [25], fertility and fecundity [26] and development of PCOS traits. In humans, a role of EDCs has been implied in the pathogenesis of several female reproductive disorders, including precocious puberty, endometriosis, female infertility, premature ovarian failure, PCOS [12] though a causal interference has not yet been established. The potential involvement of EDCs on PCOS pathogenesis is implied by animal studies of early life exposure showing the development of a PCOS like syndrome later at adult life [27]. Bisphenol A (BPA) is the most common environmental pollutant incriminated for reproductive and metabolic disorders resembling PCOS in rodents and most published literature concerning EDC and PCOS is limited to this estrogenic chemical. BPA is a ubiquitous contaminant with a broad spectrum of applications used primarily in the manufacture of polycarbonate plastic and epoxy resin [28, 29]. Due to its estrogenic properties, there is increasing concern relative to its adverse effects on normal differentiation and function of the female reproductive system. Studies of laboratory animals document BPA detrimental effects on neuroendocrine regulation of reproduction and on the ovary per se. Acceleration of puberty onset
(indicated by early vaginal opening) has been reported in rodents intrauterine exposed to environmentally relevant BPA levels [30, 31]. Changes of the HypothalamicPituitary-Ovarian axis (HPO) axis have also been reported either as interruption of gonadotrophin secretion (lower luteinizing hormone levels) [32] or as interruption of hypothalamic Gonadotropin-Releasing hormone release [33]. Moreover, developmental exposure to BPA has been related with adverse effects on several aspects of ovarian physiology from the early stage of oogenesis to oocyte maturation and fertilization [34]. A considerable number of in vitro and animal studies indicate that developmental BPA exposure disrupts oogenesis and early meiosis [35–37] as well as normal follicle growth leading to accelerated follicle transition and increased incidence of atretic follicles [38, 39]. Furthermore, ovarian steroidogenesis is also affected with increased [21, 27] or decreased androgen/estradiol levels [40] following BPA administration. Interestingly, these alterations are associated with BPA induced modifications of ovarian steroidogenic enzymes including 17β hydroxylase (P450c17), cholesterol side chain cleavage enzyme (P450scc) and steroidogenic acute regulatory protein (StAR) [21] some of which are also implicated in PCOS hyperandrogenism [41]. Taken together, the data suggest that BPA has the potency/potential to disturb reproductive function either directly at the level of the ovary by affecting follicle maturation and ovarian steroid hormone production or indirectly at the level of the hypothalamic–pituitary unit. Combined with the fact that all these processes are disturbed in PCOS, it could be assumed that BPA may act as an additional, exogenous factor to deteriorate the reproductive phenotype of the syndrome. Suggestive of this hypothesis is a study by Fernandez et al. [27] who investigated the effects of early life BPA exposure on reproductive parameters in a rat animal model. When female Sprague–Dawley rats neonatally (first 10 days postpartum) exposed to the chemical reached adulthood, they exhibited a PCOS-like syndrome characterized by biochemical hyperandrogenemia (elevated testosterone levels), unovulation, infertility, polycystic ovarian morphology and increased GnRH pulse frequency. The severity of the effects was dose-dependent with the highest dose (500 μg/50 μL) causing the full clinical phenotype due to modifications of the hypothalamic–pituitary–gonadal axis and the environmentally relevant dose (50 μg/ 50 μL) provoking subtle alterations. This animal model clearly demonstrates the development of a PCOS resembling syndrome following early life BPA exposure. This fits with the hypothesis that exposure to endocrine disrupting chemicals during sensitive developmental stages could lead to irreversible changes in endocrine systems that become evident later in adult life.
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3 Endocrine disruptor’s effects on metabolism-a link to PCOS PCOS has been typically associated with a broad spectrum of metabolic disorders and consequences including obesity, insulin resistance and compensatory hyperinsulinemia, impaired glucose metabolism and type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, hypertension, nonalcoholic fatty liver disease and high risk of cardiovascular disease [42, 43]. Metabolic aberrations co-exist and further exacerbate the reproductive features of PCOS creating a vicious cycle in which insulin resistance poses a central role [44]. There is considerable experimental evidence linking endocrine disrupting chemicals with metabolic alterations through deregulation of normal lipid and glucose homeostasis. Importantly, the world’s modern epidemics -obesity and diabetesare believed to be partly related to the increasing presence of such substances in the atmosphere [45, 46]. The so called Bobesogens^ are environmental chemicals presumed to favor obesity development through inappropriate regulation of energy and lipid metabolism [47, 48]. Many of their effects are mediated through the peroxisome proliferator-activated receptor- γ (PPAR- γ) who acts as a regulator of adipocyte differentiation [48]. Furthermore, the presence of Bdiabetogenic^ pollutants could partly explain the increasing incidence of metabolic diseases such as the metabolic syndrome and diabetes [49]. Metabolic effects may represent an indirect pathway which in combination with reproductive abnormalities favors the development of a PCOS phenotype in genetically predisposed individuals. BPA is a characteristic example of such interaction as it has been incriminated for multiple disorders including metabolic ones. Remarkably, epidemiological evidence link BPA detected in urine with cardiovascular disease, type 2 diabetes and liver enzyme abnormalities in a representative sample of adult US population [50]. Animal models of prenatal [31] and perinatal [51, 52] BPA exposure demonstrate a disruption of weight control mechanisms leading to increased adipose storage in early postnatal and adult life. These obesogenic effects may be mediated by up-regulation of adipogenesis-associated genes [52] triggering adipocyte differentiation as shown in a culture of human adipose stromal/stem cells [53]. Similarly, in vitro studies of 3T3-L1 cells highlight BPA potency to stimulate lipid accumulation in target cells involved in the metabolic syndrome [54] and to accelerate their conversion to adipocytes through the phosphatidylinositol 3-kinase pathway [55]. Furthermore, BPA is shown to control lipid homeostasis through alteration of adipokine secretion from human adipose tissue. To be more specific, in human adipose depots BPA stimulates the release of cytokines favoring adiposity and insulin resistance namely Interleukin-6 (IL-6) and Tumor Necrosis Factor α (TNF-α) [56] whereas it inhibits the release of adiponectin that protects against metabolic syndrome [57].
BPA is also associated with deregulation of glucose homeostasis through profound effects to pancreatic cells even at environmentally relevant doses [58, 59]. With respect to β-pancreatic cells function, BPA is shown in vivo to rapidly increase insulin and decrease glucose levels while in a state of prolonged exposure BPA leads to chronic hypersecretion of insulin followed by insulin resistance [58]. In a-pancreatic cells, BPA is shown to suppress glucagon secretion by inhibiting the intracellular calcium ion oscillatory pattern in the absence of glucose [59]. In experimental models, perinatal and gestational exposure to BPA is related to impaired glucose tolerance and increased insulin resistance in male adult offspring [58] while increased body weight, adiposity and lipids abnormalities have also been reported [60, 61]. It seems biological plausible that developmental exposure to BPA may disrupt glucose and lipid homeostasis, possibly contributing to the future development of metabolic syndrome, a condition commonly presented in PCOS patients. Recent data suggest that early life BPA exposure can modify the expression of metabolic genes involved in hepatic lipogenesis at weaning [52] and favor steatosis development in male adult animals [62] by epigenetic reprogramming of hepatic fatty acid β-oxidation [63]. Liver steatosis, recognized as the hepatic manifestation of metabolic syndrome, is a frequent finding in PCOS women [64]. Taken together, the above data demonstrate BPA potency to inappropriately influence adipogenesis and fat storage, to disrupt normal pancreatic cells function and favor the development of steatosis.
4 Endocrine disruptors and PCOS: human data The first study to determine serum BPA concentrations in humans was conducted by Takeuchi and colleagues more than a decade ago [65]. In this investigation, researchers measured and compared the levels of the chemical in a small-sized group of PCOS patients, a group of reproductively healthy women and a group of healthy men. BPA levels presented a gender differentiation as significantly elevated chemical levels were reported in normal men compared to normal women and in women with polycystic ovary syndrome compared to control females. Furthermore, a positive correlation was observed between BPA levels and serum total and free testosterone concentrations in all subjects implying a potential role of hyperandrogenemia on chemical’s metabolism [65]. A subsequent study of the same research group oriented to women with ovarian dysfunction included obese and nonobese PCOS women and same- weight healthy female individuals. Measurements revealed significantly increased serum BPA levels in both non-obese and obese PCOS women compared to the subgroup of non-obese control participants while they remained unchanged compared to obese controls [66]. Similarly, in this study, BPA levels were positively correlated
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Fig. 1 Possible mechanisms of Bisphenol A interaction with androgens. BPA may enhance androgen production in ovarian theca cells and may modulate their hepatic metabolism by interacting with SHBG and with enzymes regulating their hydroxylation. Furthermore, BPA and its metabolites act as androgen and progesterone receptors ligands, potentially inhibiting the endogenous native hormones. Finally,
androgens per se could down-regulate BPA liver catabolism increasing its circulating levels. AR receptors Androgen Receptors, BPA Bishpenol A, PR receptors Progesteron Receptors, SHBG Sex Hormone-Binding Globulin, UDP glucuronosyl transferase uridine diphosphate– glucuronosyl transferase
with androgens (total and free testosterone, androstenedione, dehydroepiandrosterone sulfate) and for the first time a relationship was demonstrated between BPA levels and body mass index (BMI) [66]. However, in a larger subsequent study of 71 PCOS and 100 healthy women stratified by BMI, Kandaraki et al. [67] showed that bisphenol A levels are higher in PCOS women compared to controls, independently of body weight as both lean and overweight PCOS individuals had elevated BPA levels compared to normal ovulating nonhyperandrogenemic women of matched body weight. Statistical analysis again revealed a positive correlation between BPA levels with serum testosterone (r = 0.192, P < 0.05) and androstenedione levels (r = 0.257, P < 0.05) while a positive correlation was demonstrated between BPA and the Matsuda index (r = 0.273, P < 0.05) that estimates insulin resistance. In another study of premenopausal women with PCOS, there was a positive association between BPA levels with hepatosteatosis and markers of low-grade inflammation including spleen enlargement [68]. A recent cross-sectional study contacted among female workers from BPA-exposed and unexposed factories in China, added to the evidences that BPA has a deleterious impact on human reproductive health and women’s hormone homeostasis showing that there was a significant positive association between increased urine BPA concentration and higher prolactin and progesterone levels [69]. All the above studies were conducted in adult PCOS women. Interestingly, in a group of PCOS adolescents, similar
effects were observed as elevated BPA levels were documented in PCOS adolescents compared to controls independent of obesity [70]. Similarly, BPA was strongly correlated with androgens, however, the interplay between these parameters is not yet clear, although it seems bidirectional. In vivo and in vitro data are pointing that BPA exerts its endocrine disruption activity through agonistic and antagonistic interference with the steroidal pathways of the female reproductive system.
Fig. 2 The potential pathophysiological mechanisms involved in Bisphenol A interference with PCOS pathogenesis. BPA interacts with genetic factors favoring the development of neuroendocrine, reproductive and metabolic aberrations resembling PCOS characteristics
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Multiple pathways can be affected by these interferences including binding to steroid receptors and steroid binding proteins or modulating steroidogenic enzymes in the female reproductive tissues. One hypothesis suggests that BPA directly stimulates ovarian theca cells to secrete androgens through upregulation of steroidogenic enzymes expression including 17β hydroxylase (P450c17), cholesterol side chain cleavage enzyme (P450scc) and steroidogenic acute regulatory protein (StAR) [21]. Furthermore, BPA could indirectly increase androgens by modifying their metabolism at the level of the liver through two mechanisms. The first mechanism involves interaction between BPA and sex hormone-binding globulin (SHBG) that could displace androgens and disturb androgen/estrogen balance leading to increased levels of circulating androgens [71]. The second mechanism possibly involves BPA-induced down-regulation of androgens metabolism/ hydroxylation by a decrease in testosterone 2ahydroxylase and testosterone 6b-hydroxylase activities which are the enzymes responsible for this process [72]. On the other hand, androgens per se could affect BPA metabolism by down-regulating the activity of uridine diphosphate– glucuronosyl transferase (UDP-glucuronosyltransferase, UGT) the enzyme catalyzing BPA glucuronidation by liver microsomes [73]. Recently, it has been demonstrated that structural binding of BPA, and its 1000 times more potent metabolite 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1- ene (MBP), with Androgen Receptor (AR) and Progesterone Receptor (PR), potentially inhibit the endogenous native AR and PR ligands binding and therefore resulting in target tissue dysfunction [74]. The endocrine disruption activity of BPA can occur through multiple pathways. All mechanisms possibly involved in BPA interaction with androgens are presented in Fig. 1.
The exact mechanisms linking endocrine disrupting chemicals and in particular BPA with PCOS development are yet not fully understood, making future experimental studies critical to determine the molecular basis for the observed reproductive and metabolic alterations in response to BPA as well as to determine how these effects could influence future generations through epigenetic mechanisms. It is important to bear in mind that these studies have some significant parameters to consider in their experimental design. Firstly, the dose of exposure should be relevant to humans given that several studies use toxic levels far above the environmentally equivalent ones. Secondly, exposure to a mixture of endocrine disruptors with additive or synergistic or even antagonistic effects is more likely to occur in humans rather than exposure to a sole contaminant. Thirdly, time of exposure is critical given that early life exposure could permanently alter reproductive and metabolic regulation favoring PCOS development later in adult life, while postnatal exposure could modify PCOS phenotypic expression by exacerbating its symptoms. Above all, it should always be remembered that extrapolation of data obtained from animal studies to humans has the major obstacle of species differences to overcome. It is now accepted that the natural history of PCOS could be modified by interaction with factors such as obesity and diet. Chemicals with endocrine disrupting properties and in particular BPA may represent an additional aggravating factor. Large prospective epidemiological studies using validated biomarkers of BPA exposure need to be undertaken in order to make firm conclusions about the negative impact of BPA on PCOS women. Parallel to that, laboratory studies should reveal all the molecular mechanisms underlying such a relationship. Compliance with ethical standards
5 Concluding remarks Substantial evidence from in vitro and animal studies incriminates endocrine disrupting chemicals and in particular BPA in the induction of reproductive and metabolic aberrations resembling PCOS features. All hormone-sensitive tissues implicated in reproduction such as the hypothalamic–pituitary unit and the ovary per se and in metabolism such as the adipose tissue and pancreas are experimentally deregulated by BPA (Fig. 2). Many of these effects are observed after exposure during sensitive stages of development such as fetal or neonatal life and become obvious when exposed animals reach maturity. In humans, literature is relatively limited to the documentation of elevated BPA levels in adolescents and adults with PCOS compared to healthy individuals which are positively correlated to androgen levels, implying a potential role of BPA in PCOS pathophysiology.
Conflict of interest The authors declare that they have no conflict of interest.
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