Women are exposed to endocrine disrupting chemicals (EDCs) on a daily basis. This is of concern because many EDCs are known to cause infertility and/or premature ovarian failure (early menopause). Some EDCs also may cause low estradiol (E2) levels or oxidative stress. Low E2 levels and oxidative stress are of concern because they may lead to infertility, premature menopause, or a number of adverse health outcomes such as premature aging, cardiovascular disease, mood disorders, inflammation, and osteoporosis. To date, little is known about the mechanisms by which EDCs cause low E2 levels, oxidative stress, infertility, and/or premature ovarian failure. Our preliminary studies indicate that a model organochlorine pesticide (methoxychlor;MXC), model phthalates (diethylhexyl phthalate;DEHP and mono (2-ethyl-5-hydroxyhexyl) phthalate;MEHP), and bisphenol A (BPA) reduce E2 levels and destroy antral follicles in mice. Our preliminary data also indicate that MXC, DEHP, MEHP, and BPA destroy antral follicles by inhibiting follicular growth and accelerating artesian in mice. Given that these EDCs exert similar effects on E2 levels and antral follicles, the goal of the current studies is to determine if they work through common pathways to reduce E2 production, induce slow follicular growth, and accelerate artesian, leading to infertility and premature ovarian failure. Specifically, we propose to use mice to test the hypothesis that selected model EDCs decrease E2 synthesis and/or increase E2 metabolism, leading to decreased E2 levels;and that the decreased E2 levels cause oxidative stress, which leads to slow follicular growth and artesian followed by infertility and/or premature ovarian failure. To test this hypothesis, the following specific aims will be completed: 1) determine if selected endocrine disrupting chemicals reduce E2 by inhibiting E2 synthesis and/or by increasing E2 metabolism, 2) compare the ability of selected endocrine disrupting chemicals to cause oxidative stress in antral follicles, and 3) compare the ability of selected endocrine disrupting chemicals to cause infertility and premature ovarian failure. The proposed work will increase our understanding of the mechanisms by which selected EDCs cause ovotoxicity. It is important to understand the mechanisms by which these EDCs damage the ovary because this may lead to the development of novel targets for the treatment of low E2 levels, infertility, and premature menopause induced by EDCs. By determining whether the selected EDCs work via common mechanisms, we will be able to determine if the development of novel targets for treatment of infertility and premature menopause can focus on common targets in antral follicles or if they should focus on separate intervention strategies.

Public Health Relevance

This work will greatly improve our understanding of the mechanisms by which the endocrine disrupting chemicals cause ovarian toxicity. This improved understanding may lead to the development of novel targets for the treatment of infertility and premature menopause caused by environmental chemicals.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Heindel, Jerrold
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University of Illinois Urbana-Champaign
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Hannon, Patrick R; Peretz, Jackye; Flaws, Jodi A (2014) Daily exposure to Di(2-ethylhexyl) phthalate alters estrous cyclicity and accelerates primordial follicle recruitment potentially via dysregulation of the phosphatidylinositol 3-kinase signaling pathway in adult mice. Biol Reprod 90:136
Craig, Zelieann R; Singh, Jeffrey; Gupta, Rupesh K et al. (2014) Co-treatment of mouse antral follicles with 17?-estradiol interferes with mono-2-ethylhexyl phthalate (MEHP)-induced atresia and altered apoptosis gene expression. Reprod Toxicol 45:45-51
Peretz, Jackye; Vrooman, Lisa; Ricke, William A et al. (2014) Bisphenol a and reproductive health: update of experimental and human evidence, 2007-2013. Environ Health Perspect 122:775-86
Peretz, Jackye; Flaws, Jodi A (2013) Bisphenol A down-regulates rate-limiting Cyp11a1 to acutely inhibit steroidogenesis in cultured mouse antral follicles. Toxicol Appl Pharmacol 271:249-56
Ziv-Gal, Ayelet; Craig, Zelieann R; Wang, Wei et al. (2013) Bisphenol A inhibits cultured mouse ovarian follicle growth partially via the aryl hydrocarbon receptor signaling pathway. Reprod Toxicol 42:58-67
Craig, Zelieann R; Hannon, Patrick R; Flaws, Jodi A (2013) Pregnenolone co-treatment partially restores steroidogenesis, but does not prevent growth inhibition and increased atresia in mouse ovarian antral follicles treated with mono-hydroxy methoxychlor. Toxicol Appl Pharmacol 272:780-6
Craig, Zelieann R; Hannon, Patrick R; Wang, Wei et al. (2013) Di-n-butyl phthalate disrupts the expression of genes involved in cell cycle and apoptotic pathways in mouse ovarian antral follicles. Biol Reprod 88:23
Peretz, Jackye; Neese, Steven L; Flaws, Jodi A (2013) Mouse strain does not influence the overall effects of bisphenol a-induced toxicity in adult antral follicles. Biol Reprod 89:108
Paulose, Tessie; Hannon, Patrick R; Peretz, Jackye et al. (2012) Estrogen receptor alpha overexpressing mouse antral follicles are sensitive to atresia induced by methoxychlor and its metabolites. Reprod Toxicol 33:353-60
Basavarajappa, Mallikarjuna S; Hernandez-Ochoa, Isabel; Wang, Wei et al. (2012) Methoxychlor inhibits growth and induces atresia through the aryl hydrocarbon receptor pathway in mouse ovarian antral follicles. Reprod Toxicol 34:16-21

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