Project 3: Mechanisms of In Utero BPA Exposure on Fetal Gonad Development

项目总结（见说明）： 本研究项目的主要目的是了解子宫内双酚A（BPA）暴露如何影响小鼠成年后的胚胎性腺发育和生殖。子宫内暴露于雌激素性内分泌干扰物如己烯雌酚（DES）可导致人类和啮齿类动物的性器官畸形、生殖致癌和生育缺陷。基于DES研究，有人提出，在子宫内暴露于其他内分泌干扰物，特别是那些通过雌激素受体起作用的内分泌干扰物，可能导致成年后的生殖疾病。BPA是一种用于合成塑料的化学品，当给予成年啮齿动物时，它表现出雌激素活性和对生殖的有害影响。 在孕妇血清、脐带血和胎儿血浆中检测到BPA，表明 发育中的胎儿暴露于BPA。虽然BPA对成年生殖器官的影响已经得到了广泛的研究，但子宫内BPA暴露的影响，特别是对胎儿性腺发育的影响还没有很好的了解。体外实验表明，BPA与其他雌激素化合物类似，可以与存在于胚胎小鼠性腺中的经典核雌激素受体（ER α或ER β）结合。因此，本研究项目的主要目标是检验子宫内暴露于BPA通过ER导致胎儿和成人性腺缺陷的假设。我们设计了两个具体的目标：1）研究ER α或ER β的丢失是否会导致|3）在胎儿性腺中使胚胎对BPA在生殖功能中的有害影响不敏感; 2）研究ER的过表达是否增加胚胎对子宫内BPA暴露的易感性。拟议的实验利用转基因小鼠模型的力量结合经典的毒理学方法。该项目不仅将提供动物模型来测试人类模型无法测试的假设，而且还将提供补充信息来解释形成性赠款的其他组成部分的结果。

PROJECT SUMMARY (See instnjctions): The main objective of this research project is to understand how in utero Bisphenol A (BPA) exposure affects fetal gonadal development and reproduction in adulthood in mice. In utero exposure to estrogenic endocrine disruptors such as diethylsfilbestrol (DES) is known to cause sex organ malformafion, reproductive carcinogenesis, and fertility defects in both male and female in humans and rodents. Based on DES studies, it is proposed that in utero exposure to other endocrine disruptors, particularly those that work through estrogen receptors, may lead to reproductive diseases in adulthood. BPA, a chemical used in synthesis of plastics, exhibits estrogenic activities and deleterious effects on reproduction when given to adult rodents. BPA is detected in serum of pregnant women, umbilical cord blood, and fetal plasma, indicafing that developing fetuses are exposed to BPA. Although effects of BPA on adult reproductive organs have been studied extensively, impacts of in utero BPA exposure particularly on fetal gonadal development are not well understood. In vitro experiments have suggested that BPA, similarto other estrogenic compounds, could bind to classical nuclear estrogen receptors (ERa or p), which are present in fetal mouse gonads. Therefore, the main goal ofthis Research Project is to test the hypothesis that in utero exposure to BPA causes gonadal defects in fetal and adult life via ERs. We design two specific aims to 1) investigate whether loss of ERa or |3 in fetal gonads render embryos insensitive to deleterious effects of BPA in reproductive funcstions and 2) study whether overexpression of ER increases the susceptibility of embryos to in utero exposure of BPA. The proposed experiments take advantage of the power of transgenic mouse models in combination of classic toxicological approaches. This project will not only provide animal models to test hypotheses that human models cannot, but also complementary information to interpret results of other components of the formative grant.