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.
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.
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