环境内分泌干扰物双酚A致代谢紊乱的作用机制研究

项目名称： 环境内分泌干扰物双酚A致代谢紊乱的作用机制研究

项目编号： No.81471059

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 毕宇芳

作者单位： 上海交通大学

项目金额： 80万元

中文摘要： 肥胖与2型糖尿病等代谢相关疾病受遗传与环境因素双重影响，但环境内分泌干扰物影响代谢性疾病发生的机制研究仍十分有限。本课题组前期研究发现，双酚A暴露水平与肥胖、糖脂代谢异常密切相关（JAMA2013，JCEM2013等），但机制不明。目前认为双酚A可能通过类雌激素作用激活雌激素受体（ERα）导致代谢紊乱发生；但大量基础与临床证据显示，ERα通路对机体代谢呈保护作用，且ERα敲除小鼠呈代谢紊乱状态。结合文献及本课题组前期研究基础，推测双酚A导致代谢紊乱可能通过抑制ERα信号通路或其他核受体途径。课题组建立了多种ERα信号通路干预模型，通过检测双酚A对这些模型代谢的影响，从体内、体外水平阐明双酚A影响代谢过程的分子机制，同时证实双酚A可通过改变巨噬细胞平衡、中枢食欲调节及表观遗传影响代谢过程。这些科学问题的阐述将为代谢性疾病的防治提供更多的分子靶点，有利于疾病的早期防治与综合管理。

中文关键词： 代谢紊乱；环境内分泌干扰物；双酚A；2型糖尿病；肥胖

英文摘要： In recent years, the chronic non-communicable diseases in China are facing a serious situation. Although metabolic diseases like obesity, type 2 diabetes and dyslipidemia are known to be controlled by the interactions between genetic and environmental factors, limited is known about the molecular mechanisms of the effects of environmental endocrine disruptors in metabolic diseases. We have previously found that urinary Bisphenol A (BPA) levels are close risk factors for the development of obesity and dyslipidemia. There is one opinion that BPA could mimic the effects of estrogen and activate estrogen receptor α (ERα) to cause metabolic disturbance; however, a growing body of evidence oppose this view, and support that ERα signaling pathway plays a protective role for metabolism; and ERα knockout mice show metabolic disturbance. Based on literature and our previous data, we hypothesize that BPA induced metabolic disorders may be ERα signaling pathway independent (through other nuclear receptor pathway like PPARγ), or if dependent, by inhibiting this pathway. In the present study, we have established different ERα signaling inhibition or activation models and we will detect the effects of BPA treatment on the metabolic conditions of these models to elucidate the molecular mechanism of BPA induced metabolic disorders in vivo and in vitro. Meanwhile, we will demonstrate that BPA could also affect the microphages of liver and adipose tissue, the central regulation of appetite and the epigenetic factors, thereby metabolic disturbance. This study will provide more targets for the pathogenesis and precaution of metabolic diseases.

英文关键词： metabolic diseases;environmental endocrine disruptors;Bisphenol A;type 2 diabetes;obesity