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：
8208663
负责人：
Humphrey Hung-Chang Yao
金额：
$ 7.93万
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：
2010-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8208663
关键词：
Adult Affect Animal Model Animals Behavior Binding Biological Biological Models Cells Chemicals Child Development Cognitive Cryptorchidism Defect Development Diethylstilbestrol Disease Dose Embryo Endocrine Disruptors Estrogen Nuclear Receptor 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 Methods 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 estrogenic endocrine disruptor fetal gonad function human female in utero insight male malformation man mouse model novel offspring overexpression phthalates receptor reproductive reproductive development reproductive function research study response sex tool

项目摘要

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.

该研究项目的主要目的是了解子宫双酚A（BPA）暴露如何影响小鼠成年期的胎儿性腺发育和繁殖。在子宫内暴露于雌激素内分泌众所周知，甲基stilbestrol（DES）等破坏者会引起性器官畸形，生殖男性和啮齿动物中男性和雌性的癌变以及生育缺陷。基于DES研究，有人提出，在子宫内暴露于其他内分泌破坏者中，尤其是那些通过雌激素受体可能导致成年后的生殖疾病。 BPA，一种用于合成的化学物质塑料，表现出雌激素活性和对成年啮齿动物的繁殖的有害影响。在孕妇的血清，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。尽管BPA对成人生殖器官的影响已经经过广泛研究，尤其是子宫内BPA暴露在胎儿发育中的影响不佳理解。体外实验表明，与其他雌激素化合物类似的BPA可以与胎儿性腺中存在的经典核雌激素受体（ERA或P）结合。所以，该研究项目的主要目的是检验以下假设：在子宫内暴露于BPA原因中通过ER的胎儿和成人生活中的性腺缺陷。我们设计了两个具体目的以1）调查是否丢失 ERA或B中的胎癌中的B使BPA在生殖funcStions中的有害影响不敏感 2）研究ER的过表达是否会增加胚胎对子宫暴露的敏感性 BPA。提出的实验利用了转基因小鼠模型的功能经典毒理学方法。该项目不仅将提供动物模型来检验假设人类模型不能，但也可以互补的信息来解释其他组成部分的结果形成性赠款。