Fetuses and adolescents are exposed to bisphenol A (BPA), phthalates, and high fat diets daily. This is of concern because such exposures can alter the development and function ofthe gonads, leading to infertility and/or premature reproductive senescence. The mechanisms by which BPA, phthalates, and high fat diet adversely affect gonadal development and function are unclear, but likely involve oxidative stress and epigenetic modifications. Preliminary studies indicate that BPA causes abnormal gonadal development, BPA and phthalates inhibit growth and induce death of ovarian cells through oxidative stress pathways, and high fat diet reduces female fertility in mice. The proposed studies will expand these findings by testing the hypothesis that BPA, phthalates, and high fat diet exposure interact to increase oxidative stress in developing and adolescent gonads, leading to infertility, early reproductive senescence, and transgenerational effects on fertility in the offspring. To test this hypothesis, the following specific aims will be completed: 1) determine if high fat diet and BPA/phthalate/phthalate mixture exposure increase oxidative stress in the gonads of female and male mice, 2) determine if high fat diet and BPA/phthalate/phthalate mixture exposure destroy germ cells and cause epigenetic changes known to reduce germ cell quality in the gonads of female and male mice, and 3) determine if high fat diet and BPA/phthalate/phthalate mixture exposure cause infertility and early reproductive senescence in the first and subsequent generations in mice. To complete these specific aims, gonads or mice will be exposed to BPA, diethylhexyl phthalate, or phthalate mixture during embryonic, neonatal, and adolescent life. At selected times, the gonads or mice will be subjected to measurements of oxidative stress and inflammation, epigenetic changes in DNA methylation status, fertility, and age at reproductive senescence. Collectively, the proposed work will determine the mechanishis by which the selected chemicals and high fat diet adversely affect the development and function ofthe gonads and whether chemical/diet-induced gonadal toxicity at different stages of development leads to infertility and premature reproductive senescence in adults and their offspring.

Public Health Relevance

The proposed work will determine the mechanisms by which the selected chemicals and high fat diet adversely affect the development and function of the gonads. A better understanding of the mechanisms of action of the selected chemicals and high fat diet may lead to the development of novel targets for the treatment of chemical/diet-induced infertility/premature reproductive senescence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
1P01ES022848-01
Application #
8543041
Study Section
Special Emphasis Panel (ZES1-LWJ-K (P0))
Project Start
Project End
Budget Start
2013-06-15
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$128,591
Indirect Cost
$47,512
Name
University of Illinois Urbana-Champaign
Department
Type
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Zhou, Changqing; Gao, Liying; Flaws, Jodi A (2017) Exposure to an Environmentally Relevant Phthalate Mixture Causes Transgenerational Effects on Female Reproduction in Mice. Endocrinology 158:1739-1754
Zhou, Changqing; Flaws, Jodi A (2017) Effects of an Environmentally Relevant Phthalate Mixture on Cultured Mouse Antral Follicles. Toxicol Sci 156:217-229
Barakat, Radwa; Lin, Po-Ching Patrick; Rattan, Saniya et al. (2017) Prenatal Exposure to DEHP Induces Premature Reproductive Senescence in Male Mice. Toxicol Sci 156:96-108
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Oakley, Oliver R; Kim, Kee Jun; Lin, Po-Ching et al. (2016) Estradiol Synthesis in Gut-Associated Lymphoid Tissue: Leukocyte Regulation by a Sexually Monomorphic System. Endocrinology 157:4579-4587
Li, Quanxi; Davila, Juanmahel; Kannan, Athilakshmi et al. (2016) Chronic Exposure to Bisphenol A Affects Uterine Function During Early Pregnancy in Mice. Endocrinology 157:1764-74
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

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