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

项目总结(请参阅说明)： 本研究项目的主要目的是了解宫内暴露双酚A(BPA)对成年小鼠胎儿性腺发育和生殖的影响。在子宫内暴露于雌激素内分泌干扰物，如二乙基非雌酚(DES)，已知在人类和啮齿类动物中会导致性器官畸形、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发挥作用的物质，可能会导致成年后的生殖疾病。双酚A是一种用于合成塑料的化学品，当给成年啮齿动物服用时，它会显示出雌激素活性，并对生殖产生有害影响。 在孕妇的血清、脐带血和胎儿血浆中检测到双酚A，表明 发育中的胎儿暴露在双酚A中。虽然双酚A对成人生殖器官的影响已经被广泛研究，但在宫内暴露对胎儿性腺发育的影响还不是很清楚。体外实验表明，与其他雌激素化合物类似，双酚A可以与胎儿性腺中存在的经典核雌激素受体(Era或p)结合。因此，本研究项目的主要目的是验证这样一种假设，即在子宫内暴露于BPA会通过ER导致胎儿和成人的性腺缺陷。我们设计了两个特定的目标：1)研究胎儿性腺中Era或|3的缺失是否使胚胎对双酚A在生殖功能中的有害影响不敏感；2)研究ER的过度表达是否增加了胚胎对双酚A宫内暴露的敏感性。拟议的实验利用了转基因小鼠模型的力量，结合了经典的毒理学方法。该项目不仅将提供动物模型来测试人类模型无法验证的假设，还将提供补充信息来解释形成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.