双酚A干扰稀有鮈鲫性腺类固醇激素合成和效应的DNA甲基化调控及其机制研究

项目名称： 双酚A干扰稀有鮈鲫性腺类固醇激素合成和效应的DNA甲基化调控及其机制研究

项目编号： No.31470553

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 王在照

作者单位： 西北农林科技大学

项目金额： 86万元

中文摘要： BPA在环境中普遍存在，文献及我们的预实验均表明，目前公认的BPA的毒性作用机制无法完全解释其干扰效应。我们认为BPA对DNA甲基化的影响可以更全面深入地解释BPA的效应。本项目用BPA暴露稀有鮈鲫，采用分子生物学、表观遗传学、生物化学、分析化学和组织学方法，分析DNA甲基化的调控如何参与BPA干扰性腺类固醇激素的合成及其作用，BPA对DNA甲基转移酶活性及表达的影响，BPA如何改变GSH合成而调节甲基供体SAM水平，BPA如何影响三羧酸循环的关键中间产物而调控甲基胞嘧啶羟化酶TET的活性，最终改变DNA甲基化水平。本项目首次在表观遗传层次探讨BPA对稀有鮈鲫性腺类固醇激素的合成及其作用的干扰，本项目有助于从新的角度更全面地阐明BPA的毒理机制，为BPA这种环境中普遍存在的内分泌干扰物提供敏感的表观遗传测试终点，为揭示BPA的表观遗传毒性与氧化应激及营养物质的最终代谢通路的关系提供新思路。

中文关键词： 生态毒性效应；双酚A；类固醇激素；DNA甲基化

英文摘要： Bisphenol A (BPA) is an ubiquitous compound in the environment. The previous studies and our preliminary experiments suggest that the reported properties of BPA can not completely underlie the toxicological mechanism of BPA. We speculate that the effects of BPA on DNA methylation could comprehensively and deeply elucidate the toxicological mechanism of BPA. In the present work, the rare minnow Gibiocypris rarus will be exposed to BPA at different concentrations for diverse durations. The methods of molecuar biology, epigenetics, biochemistry, analytical chemistry and histology will be used in the present study. The DNA methylation involved in BPA disturbance to steroid hormone biogenesis and the actions will be analyzed. How BPA affects activities and gene expressions of DNA methyltransferase will be investigated. The regulation of BPA exposure on production of methyl donor S-adenosyl methionine (SAM) in gonads via changes of glutathione (GSH) level will be analyzed. How BPA modulates the production of critical intermediates of the citric acid cycle involved in activity of methyl cytosine hydroxylase TET and finally the DNA methylation will be investigated. In the present study, the disturbance of BPA to biogenesis of steroid hormones and their actions will be investigated in epigenetic level for the first time. The present study will throw a new light on the toxicological mechanism for BPA. This study will provide sensitive epigenetic endpoints for BPA detection. The present findings will provide novel ideas to elucidate the relationship between the BPA's epigenetic toxicities and oxidative stress, and the final metabolic pathways.

英文关键词： ecotoxic effects;bisphenol A;steroid hormones;DNA methylation