Polycystic Ovary Syndrome: Do Endocrine-Disrupting Chemicals Play a Role?

 

 Buy Article Permissions and Reprints

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by multiple endocrine disturbances, and its underlying causes, although uncertain, are likely to be both genetic and environmental. Recently, there has been interest in whether endocrine-disrupting chemicals (EDCs) in the environment, particularly Bisphenol A (BPA), may contribute to the disorder. In animal models, exposure to BPA during the perinatal period dramatically disrupts ovarian and reproductive function in females, often at doses similar to typical levels of human exposure. BPA also appears to have obesogenic properties, disrupting normal metabolic activity and making the body prone to overweight. In humans, cross-sectional data suggest that BPA concentrations are higher in women with PCOS than in reproductively healthy women, but the direction of causality has not been established. As this research is in its infancy, additional work is needed to understand the mechanisms by which EDCs may contribute to PCOS as well as the critical periods of exposure, which may even be transgenerational. Future research should also focus on translating the promising work in animal models into longitudinal human studies and determining whether additional EDCs, beyond BPA, may be important to consider.

• References

• 1 Dasgupta S, Sirisha PV, Neelaveni K , et al. Androgen receptor CAG repeat polymorphism and epigenetic influence among the south Indian women with Polycystic Ovary Syndrome. PLoS ONE 2010; 5 (8) e12401
  CrossrefPubMedGoogle Scholar
• 2 Hickey TE, Legro RS, Norman RJ. Epigenetic modification of the X chromosome influences susceptibility to polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91 (7) 2789-2791
  CrossrefPubMedGoogle Scholar
• 3 Li Z, Huang H. Epigenetic abnormality: a possible mechanism underlying the fetal origin of polycystic ovary syndrome. Med Hypotheses 2008; 70 (3) 638-642
  CrossrefPubMedGoogle Scholar
• 4 Menke MN, Strauss III JF. Genetic approaches to polycystic ovarian syndrome. Curr Opin Obstet Gynecol 2007; 19 (4) 355-359
  CrossrefPubMedGoogle Scholar
• 5 Diamanti-Kandarakis E, Kandarakis H, Legro RS. The role of genes and environment in the etiology of PCOS. Endocrine 2006; 30 (1) 19-26
  CrossrefPubMedGoogle Scholar
• 6 Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes Rev 2013; 14 (2) 95-109
  CrossrefPubMedGoogle Scholar
• 7 Panidis D, Tziomalos K, Papadakis E, Vosnakis C, Chatzis P, Katsikis I. Lifestyle intervention and anti-obesity therapies in the polycystic ovary syndrome: impact on metabolism and fertility. Endocrine 2013; 44 (3) 583-590
  CrossrefPubMedGoogle Scholar
• 8 Moran LJ, Pasquali R, Teede HJ, Hoeger KM, Norman RJ. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril 2009; 92 (6) 1966-1982
  CrossrefPubMedGoogle Scholar
• 9 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19 (1) 41-47
  CrossrefPubMedGoogle Scholar
• 10 Azziz R, Carmina E, Dewailly D , et al; Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril 2009; 91 (2) 456-488
  CrossrefPubMedGoogle Scholar
• 11 Guerrero-Bosagna CM, Skinner MK. Environmental epigenetics and phytoestrogen/phytochemical exposures. J Steroid Biochem Mol Biol 2014; 139: 270-276
  CrossrefPubMedGoogle Scholar
• 12 Colborn T. Neurodevelopment and endocrine disruption. Environ Health Perspect 2004; 112 (9) 944-949
  PubMedGoogle Scholar
• 13 Woodruff TJ. Bridging epidemiology and model organisms to increase understanding of endocrine disrupting chemicals and human health effects. J Steroid Biochem Mol Biol 2011; 127 (1–2) 108-117
  CrossrefPubMedGoogle Scholar
• 14 Anonymous. State of the Science of Endocrine Disrupting Chemicals-2012. In: Bergman A, Heindel JJ, Jobling S. , et al. eds. Geneva, Switzerland: World Health Organization; 2012
  Google Scholar
• 15 Welshons WV, Nagel SC, vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology 2006; 147 (6, Suppl): S56-S69
  CrossrefPubMedGoogle Scholar
• 16 Matsushima A, Kakuta Y, Teramoto T , et al. Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERR gamma. J Biochem 2007; 142 (4) 517-524
  CrossrefPubMedGoogle Scholar
• 17 Koch HM, Calafat AM. Human body burdens of chemicals used in plastic manufacture. Philos Trans R Soc Lond B Biol Sci 2009; 364 (1526) 2063-2078
  CrossrefPubMedGoogle Scholar
• 18 Woodruff TJ, Zota AR, Schwartz JM. Environmental chemicals in pregnant women in the United States: NHANES 2003-2004. Environ Health Perspect 2011; 119 (6) 878-885
  CrossrefPubMedGoogle Scholar
• 19 Vandenberg LN, Colborn T, Hayes TB , et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev 2012; 33 (3) 378-455
  CrossrefPubMedGoogle Scholar
• 20 Kortenkamp A. Low dose mixture effects of endocrine disrupters: implications for risk assessment and epidemiology. Int J Androl 2008; 31 (2) 233-240
  CrossrefPubMedGoogle Scholar
• 21 Farquhar C. Introduction and history of polycystic ovary syndrome. In: Kovacs GT, Norman R, , eds. Polycystic Ovary Syndrome. 2nd ed. Cambridge, UK: Cambridge University Press; 2007
  Google Scholar
• 22 Fernández M, Bourguignon N, Lux-Lantos V, Libertun C. Neonatal exposure to bisphenol A and reproductive and endocrine alterations resembling the polycystic ovarian syndrome in adult rats. Environ Health Perspect 2010; 118 (9) 1217-1222
  CrossrefPubMedGoogle Scholar
• 23 Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV. Human exposure to bisphenol A (BPA). Reprod Toxicol 2007; 24 (2) 139-177
  CrossrefPubMedGoogle Scholar
• 24 Carwile JL, Ye X, Zhou X, Calafat AM, Michels KB. Canned soup consumption and urinary bisphenol A: a randomized crossover trial. JAMA 2011; 306 (20) 2218-2220
  CrossrefPubMedGoogle Scholar
• 25 Kang JH, Kondo F, Katayama Y. Human exposure to bisphenol A. Toxicology 2006; 226 (2–3) 79-89
  CrossrefPubMedGoogle Scholar
• 26 Rudel RA, Gray JM, Engel CL , et al. Food packaging and bisphenol A and bis(2-ethyhexyl) phthalate exposure: findings from a dietary intervention. Environ Health Perspect 2011; 119 (7) 914-920
  CrossrefPubMedGoogle Scholar
• 27 Wetherill YB, Akingbemi BT, Kanno J , et al. In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol 2007; 24 (2) 178-198
  CrossrefPubMedGoogle Scholar
• 28 Kundakovic M, Champagne FA. Epigenetic perspective on the developmental effects of bisphenol A. Brain Behav Immun 2011; 25 (6) 1084-1093
  CrossrefPubMedGoogle Scholar
• 29 Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y, Taketani Y. Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. Hum Reprod 2002; 17 (11) 2839-2841
  CrossrefPubMedGoogle Scholar
• 30 Zhou W, Liu J, Liao L, Han S, Liu J. Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells. Mol Cell Endocrinol 2008; 283 (1–2) 12-18
  CrossrefPubMedGoogle Scholar
• 31 Rosenfield RL, Barnes RB, Cara JF, Lucky AW. Dysregulation of cytochrome P450c 17 alpha as the cause of polycystic ovarian syndrome. Fertil Steril 1990; 53 (5) 785-791
  PubMedGoogle Scholar
• 32 Diamanti-Kandarakis E, Christakou C, Marinakis E. Phenotypes and environmental factors: their influence in PCOS. Curr Pharm Des 2012; 18 (3) 270-282
  CrossrefPubMedGoogle Scholar
• 33 Masuno H, Iwanami J, Kidani T, Sakayama K, Honda K. Bisphenol a accelerates terminal differentiation of 3T3-L1 cells into adipocytes through the phosphatidylinositol 3-kinase pathway. Toxicol Sci 2005; 84 (2) 319-327
  CrossrefPubMedGoogle Scholar
• 34 Hugo ER, Brandebourg TD, Woo JG, Loftus J, Alexander JW, Ben-Jonathan N. Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes. Environ Health Perspect 2008; 116 (12) 1642-1647
  CrossrefPubMedGoogle Scholar
• 35 Phrakonkham P, Viengchareun S, Belloir C, Lombès M, Artur Y, Canivenc-Lavier MC. Dietary xenoestrogens differentially impair 3T3-L1 preadipocyte differentiation and persistently affect leptin synthesis. J Steroid Biochem Mol Biol 2008; 110 (1–2) 95-103
  CrossrefPubMedGoogle Scholar
• 36 Wang J, Sun B, Hou M, Pan X, Li X. The environmental obesogen bisphenol A promotes adipogenesis by increasing the amount of 11β-hydroxysteroid dehydrogenase type 1 in the adipose tissue of children. Int J Obes (Lond) 2013; 37 (7) 999-1005
  CrossrefPubMedGoogle Scholar
• 37 Nadal A, Alonso-Magdalena P, Soriano S, Quesada I, Ropero AB. The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Mol Cell Endocrinol 2009; 304 (1–2) 63-68
  CrossrefPubMedGoogle Scholar
• 38 Alonso-Magdalena P, Ropero AB, Carrera MP , et al. Pancreatic insulin content regulation by the estrogen receptor ER α. PLoS ONE 2008; 3 (4) e2069
  CrossrefPubMedGoogle Scholar
• 39 Bastos Sales L, Kamstra JH, Cenijn PH, van Rijt LS, Hamers T, Legler J. Effects of endocrine disrupting chemicals on in vitro global DNA methylation and adipocyte differentiation. Toxicol In Vitro 2013; 27 (6) 1634-1643
  CrossrefPubMedGoogle Scholar
• 40 Anway MD, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors. Endocrinology 2006; 147 (6, Suppl): S43-S49
  CrossrefPubMedGoogle Scholar
• 41 Shi D, Vine DF. Animal models of polycystic ovary syndrome: a focused review of rodent models in relationship to clinical phenotypes and cardiometabolic risk. Fertil Steril 2012; 98 (1) 185-193
  CrossrefPubMedGoogle Scholar
• 42 Padmanabhan V, Veiga-Lopez A. Sheep models of polycystic ovary syndrome phenotype. Mol Cell Endocrinol 2013; 373 (1–2) 8-20
  CrossrefPubMedGoogle Scholar
• 43 Abbott DH, Barnett DK, Bruns CM, Dumesic DA. Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?. Hum Reprod Update 2005; 11 (4) 357-374
  CrossrefPubMedGoogle Scholar
• 44 de Zegher F, Lopez-Bermejo A, Ibáñez L. Adipose tissue expandability and the early origins of PCOS. Trends Endocrinol Metab 2009; 20 (9) 418-423
  CrossrefPubMedGoogle Scholar
• 45 Virtue S, Vidal-Puig A. It's not how fat you are, it's what you do with it that counts. PLoS Biol 2008; 6 (9) e237
  CrossrefPubMedGoogle Scholar
• 46 Newbold RR, Bullock BC, McLachlan JA. Uterine adenocarcinoma in mice following developmental treatment with estrogens: a model for hormonal carcinogenesis. Cancer Res 1990; 50 (23) 7677-7681
  PubMedGoogle Scholar
• 47 Newbold RR, Banks EP, Bullock B, Jefferson WN. Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Res 2001; 61 (11) 4325-4328
  PubMedGoogle Scholar
• 48 Newbold RR, Jefferson WN, Padilla-Banks E. Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol 2007; 24 (2) 253-258
  CrossrefPubMedGoogle Scholar
• 49 Newbold RR, Jefferson WN, Padilla-Banks E. Prenatal exposure to bisphenol A at environmentally relevant doses adversely affects the murine female reproductive tract later in life. Environ Health Perspect 2009; 117 (6) 879-885
  CrossrefPubMedGoogle Scholar
• 50 Honma S, Suzuki A, Buchanan DL, Katsu Y, Watanabe H, Iguchi T. Low dose effect of in utero exposure to bisphenol A and diethylstilbestrol on female mouse reproduction. Reprod Toxicol 2002; 16 (2) 117-122
  CrossrefPubMedGoogle Scholar
• 51 Howdeshell KL, Hotchkiss AK, Thayer KA, Vandenbergh JG, vom Saal FS. Exposure to bisphenol A advances puberty. Nature 1999; 401 (6755): 763-764
  CrossrefPubMedGoogle Scholar
• 52 Markey CM, Luque EH, Munoz De Toro M, Sonnenschein C, Soto AM. In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod 2001; 65 (4) 1215-1223
  PubMedGoogle Scholar
• 53 Rubin BS, Murray MK, Damassa DA, King JC, Soto AM. Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environ Health Perspect 2001; 109 (7) 675-680
  CrossrefPubMedGoogle Scholar
• 54 Schönfelder G, Flick B, Mayr E, Talsness C, Paul M, Chahoud I. In utero exposure to low doses of bisphenol A lead to long-term deleterious effects in the vagina. Neoplasia 2002; 4 (2) 98-102
  CrossrefPubMedGoogle Scholar
• 55 Schönfelder G, Friedrich K, Paul M, Chahoud I. Developmental effects of prenatal exposure to bisphenol A on the uterus of rat offspring. Neoplasia 2004; 6 (5) 584-594
  CrossrefPubMedGoogle Scholar
• 56 Vandenberg LN, Maffini MV, Wadia PR, Sonnenschein C, Rubin BS, Soto AM. Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland. Endocrinology 2007; 148 (1) 116-127
  CrossrefPubMedGoogle Scholar
• 57 Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ Health Perspect 2008; 116 (1) 39-44
  PubMedGoogle Scholar
• 58 Program NT. Low Dose Endocrine Disruptors Peer Review. Research Triangle Park, NC: National Institute of Environmental Health Sciences; 2001
  Google Scholar
• 59 Adewale HB, Jefferson WN, Newbold RR, Patisaul HB. Neonatal bisphenol-a exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropin-releasing hormone neurons. Biol Reprod 2009; 81 (4) 690-699
  CrossrefPubMedGoogle Scholar
• 60 Kato H, Ota T, Furuhashi T, Ohta Y, Iguchi T. Changes in reproductive organs of female rats treated with bisphenol A during the neonatal period. Reprod Toxicol 2003; 17 (3) 283-288
  CrossrefPubMedGoogle Scholar
• 61 Markey CM, Coombs MA, Sonnenschein C, Soto AM. Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs. Evol Dev 2003; 5 (1) 67-75
  CrossrefPubMedGoogle Scholar
• 62 Fernández M, Bianchi M, Lux-Lantos V, Libertun C. Neonatal exposure to bisphenol A alters reproductive parameters and gonadotropin releasing hormone signaling in female rats. Environ Health Perspect 2009; 117 (5) 757-762
  CrossrefPubMedGoogle Scholar
• 63 Nguyen RH, Umbach DM, Parad RB, Stroehla B, Rogan WJ, Estroff JA. US assessment of estrogen-responsive organ growth among healthy term infants: piloting methods for assessing estrogenic activity. Pediatr Radiol 2011; 41 (5) 633-642
  CrossrefPubMedGoogle Scholar
• 64 Kandaraki E, Chatzigeorgiou A, Livadas S , et al. Endocrine disruptors and polycystic ovary syndrome (PCOS): elevated serum levels of bisphenol A in women with PCOS. J Clin Endocrinol Metab 2011; 96 (3) E480-E484
  CrossrefPubMedGoogle Scholar
• 65 Takeuchi T, Tsutsumi O, Ikezuki Y, Takai Y, Taketani Y. Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. Endocr J 2004; 51 (2) 165-169
  CrossrefPubMedGoogle Scholar
• 66 Tarantino G, Valentino R, Di Somma C , et al. Bisphenol A in polycystic ovary syndrome and its association with liver-spleen axis. Clin Endocrinol (Oxf) 2013; 78 (3) 447-453
  CrossrefPubMedGoogle Scholar
• 67 Déchaud H, Ravard C, Claustrat F, de la Perrière AB, Pugeat M. Xenoestrogen interaction with human sex hormone-binding globulin (hSHBG). Steroids 1999; 64 (5) 328-334
  CrossrefPubMedGoogle Scholar
• 68 Hanioka N, Jinno H, Nishimura T, Ando M. Suppression of male-specific cytochrome P450 isoforms by bisphenol A in rat liver. Arch Toxicol 1998; 72 (7) 387-394
  CrossrefPubMedGoogle Scholar
• 69 Yokota H, Iwano H, Endo M , et al. Glucuronidation of the environmental oestrogen bisphenol A by an isoform of UDP-glucuronosyltransferase, UGT2B1, in the rat liver. Biochem J 1999; 340 (Pt 2) 405-409
  CrossrefPubMedGoogle Scholar
• 70 Takeuchi T, Tsutsumi O, Ikezuki Y , et al. Elevated serum bisphenol A levels under hyperandrogenic conditions may be caused by decreased UDP-glucuronosyltransferase activity. Endocr J 2006; 53 (4) 485-491
  CrossrefPubMedGoogle Scholar
• 71 Guillemette C, Lévesque E, Beaulieu M, Turgeon D, Hum DW, Bélanger A. Differential regulation of two uridine diphospho-glucuronosyltransferases, UGT2B15 and UGT2B17, in human prostate LNCaP cells. Endocrinology 1997; 138 (7) 2998-3005
  PubMedGoogle Scholar
• 72 Takeuchi T, Tsutsumi O. Serum bisphenol A concentrations showed gender differences, possibly linked to androgen levels. Biochem Biophys Res Commun 2002; 291 (1) 76-78
  CrossrefPubMedGoogle Scholar
• 73 Takeuchi T, Tsutsumi O, Nakamura N , et al. Gender difference in serum bisphenol A levels may be caused by liver UDP-glucuronosyltransferase activity in rats. Biochem Biophys Res Commun 2004; 325 (2) 549-554
  CrossrefPubMedGoogle Scholar
• 74 Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 2012; 33 (6) 981-1030
  CrossrefPubMedGoogle Scholar
• 75 Willis D, Mason H, Gilling-Smith C, Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab 1996; 81 (1) 302-309
  PubMedGoogle Scholar
• 76 Zawadzki J, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens J, Haseltine F, , et al. eds. Polycystic Ovary Syndrome. Boston, MA: Blackwell Scientific Publications; 1990: 377-384
  Google Scholar
• 77 Moran L, Teede H. Metabolic features of the reproductive phenotypes of polycystic ovary syndrome. Hum Reprod Update 2009; 15 (4) 477-488
  CrossrefPubMedGoogle Scholar
• 78 Diamanti-Kandarakis E, Panidis D. Unravelling the phenotypic map of polycystic ovary syndrome (PCOS): a prospective study of 634 women with PCOS. Clin Endocrinol (Oxf) 2007; 67 (5) 735-742
  CrossrefPubMedGoogle Scholar
• 79 Rizzo M, Berneis K, Hersberger M , et al. Milder forms of atherogenic dyslipidemia in ovulatory versus anovulatory polycystic ovary syndrome phenotype. Hum Reprod 2009; 24 (9) 2286-2292
  CrossrefPubMedGoogle Scholar
• 80 Pasquali R, Gambineri A, Pagotto U. The impact of obesity on reproduction in women with polycystic ovary syndrome. BJOG 2006; 113 (10) 1148-1159
  CrossrefPubMedGoogle Scholar
• 81 Vigil P, Contreras P, Alvarado JL, Godoy A, Salgado AM, Cortés ME. Evidence of subpopulations with different levels of insulin resistance in women with polycystic ovary syndrome. Hum Reprod 2007; 22 (11) 2974-2980
  CrossrefPubMedGoogle Scholar
• 82 Janesick A, Blumberg B. Endocrine disrupting chemicals and the developmental programming of adipogenesis and obesity. Birth Defects Res C Embryo Today 2011; 93 (1) 34-50
  CrossrefPubMedGoogle Scholar
• 83 Vom Saal FS, Nagel SC, Coe BL, Angle BM, Taylor JA. The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity. Mol Cell Endocrinol 2012; 354 (1–2) 74-84
  CrossrefPubMedGoogle Scholar
• 84 Harley KG, Aguilar Schall R, Chevrier J , et al. Prenatal and postnatal bisphenol A exposure and body mass index in childhood in the CHAMACOS cohort. Environ Health Perspect 2013; 121 (4) 514-520 , e1–e6
  CrossrefPubMedGoogle Scholar
• 85 Li DK, Miao M, Zhou Z , et al. Urine bisphenol-A level in relation to obesity and overweight in school-age children. PLoS ONE 2013; 8 (6) e65399
  CrossrefPubMedGoogle Scholar
• 86 Wang HX, Zhou Y, Tang CX, Wu JG, Chen Y, Jiang QW. Association between bisphenol A exposure and body mass index in Chinese school children: a cross-sectional study. Environ Health 2012; 11: 79
  CrossrefPubMedGoogle Scholar
• 87 Trasande L, Attina TM, Blustein J. Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents. JAMA 2012; 308 (11) 1113-1121
  CrossrefPubMedGoogle Scholar
• 88 Carwile JL, Michels KB. Urinary bisphenol A and obesity: NHANES 2003-2006. Environ Res 2011; 111 (6) 825-830
  CrossrefPubMedGoogle Scholar
• 89 Melzer D, Rice NE, Lewis C, Henley WE, Galloway TS. Association of urinary bisphenol A concentration with heart disease: evidence from NHANES 2003/06. PLoS ONE 2010; 5 (1) e8673
  CrossrefPubMedGoogle Scholar
• 90 Melzer D, Osborne NJ, Henley WE , et al. Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women. Circulation 2012; 125 (12) 1482-1490
  CrossrefPubMedGoogle Scholar
• 91 Shankar A, Teppala S, Sabanayagam C. Bisphenol A and peripheral arterial disease: results from the NHANES. Environ Health Perspect 2012; 120 (9) 1297-1300
  CrossrefPubMedGoogle Scholar
• 92 Sabanayagam C, Teppala S, Shankar A. Relationship between urinary bisphenol A levels and prediabetes among subjects free of diabetes. Acta Diabetol 2013; 50 (4) 625-631
  CrossrefPubMedGoogle Scholar
• 93 Lang IA, Galloway TS, Scarlett A , et al. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 2008; 300 (11) 1303-1310
  CrossrefPubMedGoogle Scholar
• 94 Wang T, Li M, Chen B , et al. Urinary bisphenol A (BPA) concentration associates with obesity and insulin resistance. J Clin Endocrinol Metab 2012; 97 (2) E223-E227
  CrossrefPubMedGoogle Scholar
• 95 Shankar A, Teppala S. Urinary bisphenol A and hypertension in a multiethnic sample of US adults. J Environ Public Health 2012; 2012: 481641
  PubMedGoogle Scholar
• 96 Batista TM, Alonso-Magdalena P, Vieira E , et al. Short-term treatment with bisphenol-A leads to metabolic abnormalities in adult male mice. PLoS ONE 2012; 7 (3) e33814
  CrossrefPubMedGoogle Scholar
• 97 Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E, Nadal A. The estrogenic effect of bisphenol A disrupts pancreatic β-cell function in vivo and induces insulin resistance. Environ Health Perspect 2006; 114 (1) 106-112
  CrossrefPubMedGoogle Scholar
• 98 Ropero AB, Alonso-Magdalena P, García-García E, Ripoll C, Fuentes E, Nadal A. Bisphenol-A disruption of the endocrine pancreas and blood glucose homeostasis. Int J Androl 2008; 31 (2) 194-200
  CrossrefPubMedGoogle Scholar
• 99 Alonso-Magdalena P, Vieira E, Soriano S , et al. Bisphenol A exposure during pregnancy disrupts glucose homeostasis in mothers and adult male offspring. Environ Health Perspect 2010; 118 (9) 1243-1250
  CrossrefPubMedGoogle Scholar
• 100 Angle BM, Do RP, Ponzi D , et al. Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation. Reprod Toxicol 2013; 42: 256-268
  CrossrefPubMedGoogle Scholar
• 101 Makaji E, Raha S, Wade MG, Holloway AC. Effect of environmental contaminants on Beta cell function. Int J Toxicol 2011; 30 (4) 410-418
  CrossrefPubMedGoogle Scholar
• 102 Escobar-Morreale HF, San Millán JL. Abdominal adiposity and the polycystic ovary syndrome. Trends Endocrinol Metab 2007; 18 (7) 266-272
  CrossrefPubMedGoogle Scholar
• 103 Legro RS. Obesity and PCOS: implications for diagnosis and treatment. Semin Reprod Med 2012; 30 (6) 496-506
  Article in Thieme ConnectPubMedGoogle Scholar
• 104 Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS ONE 2013; 8 (1) e55387
  CrossrefPubMedGoogle Scholar
• 105 Tracey R, Manikkam M, Guerrero-Bosagna C, Skinner MK. Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. Reprod Toxicol 2013; 36: 104-116
  CrossrefPubMedGoogle Scholar
• 106 Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations. PLoS ONE 2012; 7 (9) e46249
  CrossrefPubMedGoogle Scholar
• 107 Nilsson E, Larsen G, Manikkam M, Guerrero-Bosagna C, Savenkova MI, Skinner MK. Environmentally induced epigenetic transgenerational inheritance of ovarian disease. PLoS ONE 2012; 7 (5) e36129
  CrossrefPubMedGoogle Scholar
• 108 Cory-Slechta DA. Studying toxicants as single chemicals: does this strategy adequately identify neurotoxic risk?. Neurotoxicology 2005; 26 (4) 491-510
  CrossrefPubMedGoogle Scholar