从胰岛素信号转导通路探讨BPA促进动脉粥样硬化的作用机制

项目名称： 从胰岛素信号转导通路探讨BPA促进动脉粥样硬化的作用机制

项目编号： No.21477124

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 化学工业

项目作者： 董四君

作者单位： 中国科学院城市环境研究所

项目金额： 86万元

中文摘要： 双酚A（BPA）是典型的环境内分泌干扰物。大量流行病学调查证实BPA暴露与动脉粥样硬化（AS）的发生存在显著正相关，但对于危害现象的分子毒理机制报道较少。胰岛素抵抗可导致动脉血管胰岛素信号受损，进而破坏血管壁舒缩功能、促进血管平滑肌细胞增殖、诱导单核-巨噬细胞凋亡，在AS的发生发展过程中发挥重要作用。现已证实BPA可通过抑制胰岛素信号诱发机体胰岛素抵抗，所以本项目拟以渡边可遗传高脂血症（WHHL）家兔为研究对象，确定BPA暴露引发WHHL家兔胰岛素抵抗和AS的风险和量效关系；阐明BPA暴露致AS过程中受胰岛素信号通路调控的关键靶基因及其信号网络；利用离体培养的血管内皮细胞、平滑肌细胞及巨噬细胞模型，比较过表达或抑制筛选靶基因前后BPA对血管细胞脂肪病变、炎症、增殖、凋亡等的影响，确证BPA通过干扰胰岛素信号转导诱发AS的分子机制。项目有望为环境因素致AS的发病机制研究提供新的思路与线索。

中文关键词： 双酚A；毒性效应；信号通路；分子机制；环境健康

英文摘要： Bisphenol A (BPA) is one of environmental endocrine disrupting chemicals that is present ubiquitously in daily life. Although many epidemiologic studies have established the association between BPA exposure and the development of atherosclerotic cardiovascular disease, the underlying mechanisms clarified by in vitro studies or in vivo experimental work in animals are limited. As we known, normal insulin signaling in classical insulin target organs such as liver, muscle, and adipose are important for maintaining the whole body glucose homeostasis. And there are increasing studies suggest that defective insulin signaling in cells of the arterial wall including macrophages may promote the development of atherosclerosis. In previous study, exposure to BPA has been shown to induce insulin resistance by disrupting insulin signaling in peripheral tissues in rat or mice model. Because that the rabbit is considered more suitable animal model for studying cardiovascular disease, the present study selected a Watanabe heritable hyperlipidemic (WHHL) rabbit model, which is deficient for LDL receptor function, to test whether exposure to BPA was able to induce or/and promote the development of atherosclerosis, and if so, whether these adverse effects were mediated by impaired regulation of insulin signaling. We firstly tested the effects of exposure to BPA on glucose homeostasis and atherosclerotic lesions in the WHHL rabbits. Then, effects of BPA on components/modulators of the insulin signaling pathway were screened and identified in both classic insulin-sensitive organs and arterial vascular cell (including endohtelial, smooth muscle and macrophage foam cells) by performing modern molecular biology experiments. After that, cell culture and intervention experiments were performed in vitro to ensure the possibility that exposure to BPA worsened atherosclerosis by selectively inhibiting insulin signaling. Taken together, this study is expected to address the mechanism of BPA-induced atherosclerosis at molecular levels, furthermore, create new insights into the role of environmental factors on the onset of atherosclerosis.

英文关键词： Bisphenol A;Toxic effect;Signaling Pathway;Molecular mechanism;Environmental health