Project 2: Endocrine Disrupting Chemicals, Diet and Gonadal Toxicity (Flaws)

胎儿和青少年每天都会接触到双酚A(BPA)、邻苯二甲酸盐和高脂肪饮食。这一点令人担忧，因为这种暴露会改变性腺的发育和功能，导致不育症和/或过早的生殖衰老。双酚A、邻苯二甲酸盐和高脂饮食对性腺发育和功能的负面影响机制尚不清楚，但可能涉及氧化应激和表观遗传修饰。初步研究表明，双酚A导致性腺发育异常，双酚A和邻苯二甲酸酯通过氧化应激途径抑制卵巢细胞的生长并诱导其死亡，高脂饮食降低小鼠的雌性生育力。拟议的研究将通过检验以下假设来扩大这些发现：双酚A、邻苯二甲酸盐和高脂肪饮食暴露相互作用，增加发育中和青春期性腺的氧化应激，导致不育症、早期生殖衰老，并对后代的生育能力产生跨代影响。为了验证这一假说，将完成下列具体目标：1)确定高脂饮食和BPA/邻苯二甲酸盐/邻苯二甲酸盐混合物暴露是否会增加雌性和雄性小鼠性腺的氧化应激；2)确定高脂饮食和BPA/邻苯二甲酸盐/邻苯二甲酸盐混合物暴露是否会破坏生殖细胞并引起已知可降低雌性和雄性小鼠性腺生殖细胞质量的表观遗传学变化；3)确定高脂肪饮食和BPA/邻苯二甲酸盐/邻苯二甲酸盐混合物暴露是否会导致第一代和后续小鼠不育和提早生殖衰老。为了完成这些特定的目标，在胚胎、新生儿和青春期，性腺或小鼠将暴露在双酚A、邻苯二甲酸二乙基己酯或邻苯二甲酸盐混合物中。在选定的时间，性腺或小鼠将接受氧化应激和炎症的测量，DNA甲基化状态的表观遗传变化，生育能力，以及生殖衰老时的年龄。总的来说，拟议的工作将确定选定的化学品和高脂肪饮食对性腺的发育和功能产生不利影响的机制，以及化学品/饮食在不同发育阶段诱导的性腺毒性是否会导致成年及其后代不育和过早生殖衰老。

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.