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

项目3：子宫内BPA暴露对胎儿性腺发育的机制

基本信息

批准号：
7846644
负责人：
Humphrey Hung-Chang Yao
金额：
$ 9.88万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846644
关键词：
Adult Affect Animal Model Animals Behavior Binding Biological Biological Models Cells Chemicals Cognitive Cryptorchidism Defect Development Diethylstilbestrol Disease Dose Embryo Endocrine Endocrine Disruptors Estrogen Nuclear Receptor Estrogen Receptor alpha Estrogen Receptors Estrogens Exhibits Exposure to Female Fertility Fetus Genes Genetic Genetic Models Genetic Polymorphism Genetic Variation Germ Cells Goals Gonadal structure Grant Hormones Human In Vitro Individual Knock-out Knockout Mice Lead Life Link Modeling Mus Organ Ovary Perinatal Exposure Plasma Plastics Predisposing Factor Predisposition Pregnant Women Process Production Reproduction Research Project Grants Rodent Serum Signal Pathway Somatic Cell Staging Structure Testing Testis Transgenic Mice Transgenic Organisms Umbilical Cord Blood Work base bisphenol A carcinogenesis cognitive function design estrogenic activity fetal gonad function human female in utero insight male mouse model offspring overexpression receptor reproductive reproductive development research study response sex tool

项目摘要

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.

项目摘要（参见说明）：该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期胎儿性腺的发育和生殖。众所周知，在子宫内暴露于雌激素内分泌干扰物，如己烯雌酚 (DES) 会导致人类和啮齿类动物的性器官畸形、生殖癌和生育缺陷。根据 DES 研究，有人提出，在子宫内接触其他内分泌干扰物，特别是那些通过雌激素受体发挥作用的内分泌干扰物，可能会导致成年后出现生殖疾病。 BPA 是一种用于合成塑料的化学物质，当给予成年啮齿动物时，会表现出雌激素活性，并对生殖产生有害影响。在孕妇血清、脐带血和胎儿血浆中检测到 BPA，表明发育中的胎儿会接触 BPA。尽管 BPA 对成人生殖器官的影响已得到广泛研究，但子宫内 BPA 暴露的影响，特别是对胎儿性腺发育的影响尚不清楚。体外实验表明，与其他雌激素化合物类似，BPA 可以与胎儿小鼠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标是检验以下假设：子宫内接触 BPA 通过 ER 导致胎儿和成人性腺缺陷。我们设计了两个具体目标：1) 研究胎儿性腺中 ERa 或 |3 的缺失是否会使胚胎对 BPA 对生殖功能的有害影响不敏感；2) 研究 ER 的过度表达是否会增加胚胎对子宫内接触 BPA 的敏感性。所提出的实验利用了转基因小鼠模型结合经典毒理学方法的力量。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，还将提供补充信息来解释形成性资助其他组成部分的结果。