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

这项研究项目的主要目的是了解子宫内暴露的双酚A(BPA)对 小鼠成年期胎儿性腺发育与生殖。宫内暴露于雌激素内分泌 已知的干扰物如己烯雌酚(DES)会导致性器官畸形、生殖 人类和啮齿动物雄性和雌性的致癌和生育缺陷。基于DES研究， 有人建议，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，可能会导致成年后的生殖疾病。双酚A，一种用于合成 塑料，当给成年啮齿动物服用时，表现出雌激素活性和对生殖的有害影响。 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。尽管双酚A对成人生殖器官的影响已经被 广泛研究表明，宫内暴露双酚A对胎儿性腺发育的影响不是很好。 明白了。体外实验表明，与其他雌激素化合物类似，双酚A可以 与经典的核雌激素受体(era或p)结合，后者存在于胎鼠性腺中。因此， 这项研究项目的主要目标是检验这样一种假设，即子宫内暴露于BPA会导致 胎儿和成人性腺缺陷通过ER。我们设计了两个具体的目标来1)调查 胎儿性腺中的Era或B使胚胎对双酚A在生殖功能中的有害影响不敏感 以及2)研究过表达ER是否增加胚胎对宫内暴露的易感性 双酚A。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假设 人体模型不能，但也可以补充信息来解释其他组件的结果 形成性赠款。

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 diethylstilbestrol (DES) is known to cause sex organ malformation, 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, indicating 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, similar to other estrogenic compounds, could bind to classical nuclear estrogen receptors (ERa or p), which are present in fetal mouse gonads. Therefore, the main goal of this 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 B 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.