基于DNA甲基化的双酚A内分泌干扰毒性机制研究

Endocrine disrupting compounds (EDCs) exist widely in environment, and have been proposed to be a potential risk to public health. EDCs were reported to disturb the normal function of organism transgenerationally and the toxic mechanism of EDCs has attracted many scientists’ attention. Study on epigenetic modifications, such as DNA methylation, may provide a new way for elucidation of the inherited toxic mechanism of typical EDCs. In this study, epigenetic mechanism in the pathogenesis of typical EDCs is discussed. Alterations of global DNA methylation level and site-specific DNA methylation status in BPA treated cell lines will be analyzed. The activity and expression of DNA methyltransferases are evaluated in BPA treated cell lines. Potential molecular path of BPA induced endocrine function disorder may be found by the methylation landscape analysis. We also hope to screen specific genes which are sensitive to typical EDCs in DNA methylation level as new molecular biological markers for the toxicology evaluation of EDCs. Our study may provide scientific basis and technical support for the human health risk assessment of typical EDCs.

内分泌干扰物在环境中广泛存在，破坏生物体正常的生理功能，严重威胁人体健康，其内分泌干扰毒性及致病机制日益受到人们的关注。本项目从表观遗传学角度分析环境内分泌干扰物对DNA甲基化这一典型表观遗传修饰形式的影响，为内分泌干扰物可跨代遗传的毒性机制研究提供新的途径。课题选取双酚A为代表，研究内分泌干扰物对激素敏感细胞基因组DNA整体甲基化水平及特定基因启动子区甲基化水平的影响；分析暴露细胞甲基化图谱的变化规律以及DNA甲基转移酶等相关蛋白在DNA甲基化模式改变中的作用，深入研究双酚A内分泌干扰物毒性效应的可能分子路径；并根据暴露细胞中特定位点甲基化状态的差异，筛选内分泌干扰物的敏感基因作为其毒性监测的可能分子指标。本项目的开展有望为典型环境内分泌干扰物的健康风险评估提供理论依据和数据支持。

环境内分泌干扰物可扰乱生物体正常生理功能，威胁人体健康，其内分泌干扰毒性和致病机制日益受到人们关注。研究报道双酚A等环境内分泌干扰物对胚胎生长发育的影响可跨代遗传，而表观遗传学的发展为其跨代遗传现象提供新的研究途径。本项目以双酚A为代表研究环境内分泌干扰物对DNA甲基化这一典型表观遗传修饰形式的影响，从表观遗传学角度分析环境内分泌干扰物对生物体生理功能的影响。研究结果显示双酚A低剂量暴露可导致MCF-7细胞中肿瘤相关基因表达的改变，促进细胞增殖；双酚A长期低剂量暴露虽然对MCF-7细胞基因组DNA的整体甲基化水平、5-羟甲基胞嘧啶含量以及DNA甲基转移酶的表达无显著性影响，但低浓度双酚A长期暴露可导致特定位点甲基化状态的改变，包括肿瘤抑制基因（FOXK2，LKB1，LMX1A，CUGBP2）的甲基化上调及肿瘤生长调控相关基因（PTPRN2，TRIM27，BCAS3）的甲基化下调，关键基因甲基化模式的变化可能加速肿瘤细胞生长和转移。研究双酚A暴露细胞基因组范围内DNA甲基化模式的改变，筛选内分泌干扰物敏感基因，希望为环境内分泌干扰物的表观遗传毒性机制研究及健康风险评估提供数据支撑。