低剂量双酚A生殖毒性的分子和表观遗传作用机制

项目名称： 低剂量双酚A生殖毒性的分子和表观遗传作用机制

项目编号： No.41271491

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 天文学、地球科学

项目作者： 黄长江

作者单位： 温州医科大学

项目金额： 75万元

中文摘要： 内分沁干扰物双酚A（BPA）因在环境和人体内普遍存在而被认为是现代生殖健康问题的主要因素之一。其结构与雌激素相似，因而多数研究均假设BPA是通过与雌激素受体（ERs）结合而作用于靶基因的。然而BPA在人体内的低含量及与ERs的弱亲和力让人对此产生质疑。最近研究雌激素相关受体ERRγ（与BPA的结合力更强且缺乏内源性配体）更有可能是BPA的作用受体。针对这一研究空白，本项目以斑马鱼为模式动物，采用传统毒理学和现代分子生物学研究手段，通过低剂量BPA于敏感窗口的慢性暴毒：1）识别低剂量（环境浓度值）BPA生殖毒性的形态/生理表型及特征基因表型；2）阐释低剂量BPA在敏感窗口期暴毒所引发的生殖毒性的分子作用受体；3）探索BPA生殖毒性是否存在表观遗传作用机制。研究结果能诠释以BPA为代表的一些典型内分沁干扰物的生殖毒性作用机制，而且可为这些化合物对生物和人类生殖健康的风险评价提供重要的科学依据。

中文关键词： 双酚A；斑马鱼；慢性暴露；生殖毒性；Wnt信号通路

英文摘要： The plastic monomer and plasticizer bisphenol A (BPA) is an endocrine disruptor chemicals (EDCs) that is ubiquitous in environment and human body. The structure similarity between BPA and the 17β-estradiol (E2) has prompted researchers to suspect that BPA is one of the main causative factors for the continuous decline of human reproductive health. Previous research has been driven by the assumption that BPA acts as an estrogen disruptor through binding with classical nuclear estrogen receptors (ERs). However, BPA was normally detected at low doses in human body, and it has also been shown to have weak binding affinity with ERs. It thus seems impossible for BPA to compete with E2 for binding sites on ERs and initiate gene expression changes in vivo. More recent studies indicate that BPA exhibits very strong binding affinity for estrogen related receptor gamma (ERRγ) while ERRγ is an orphan nuclear receptor that has no known endogenous ligand, suggesting BPA may affect reproduction through ERRγ. Currently, it is unknown whether BPA exerts its reproductive toxicity through ERs or ERRγ. To bridge this gap, our proposal thus hypothesize that low dose BPA-induced reproductive toxicity is mediated through ERRγ. This proposal will use zebrafish as the model animal and take the advantage of the modern molecular and epige

英文关键词： bisphenol A；zebrafish；chronic exposure；reproductive toxicity；Wnt signaling