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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES019178-03
Application #
8249425
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Heindel, Jerrold
Project Start
2010-06-04
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$454,172
Indirect Cost
$167,628
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Strakovsky, Rita S; Wang, Huan; Engeseth, Nicki J et al. (2015) Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis. Toxicol Appl Pharmacol 284:101-12
Tannenbaum, Lawrence V; Flaws, Jodi A (2015) Exposure Duration-Dependent Ovarian Recovery in Methoxychlor-Treated Mice. Birth Defects Res B Dev Reprod Toxicol 104:238-43
Hannon, Patrick R; Brannick, Katherine E; Wang, Wei et al. (2015) Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces atresia, and inhibits steroid hormone production in cultured mouse antral follicles. Toxicol Appl Pharmacol 284:42-53

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