砷暴露对精子组蛋白修饰的影响及其男（雄）性生殖毒性机制研究

砷是环境中广泛存在的一种类金属污染物，其人群暴露以及由此产生的健康效应，特别是对男性生殖健康的影响已越来越为人们所关注。流行病学研究表明，砷暴露与男性精子质量下降具有显著的相关性，但其分子机理尚不清楚。基于组蛋白甲基化和乙酰化在精子发生、发育过程中的重要作用，以及砷可改变细胞组蛋白修饰特征的实验证据，本项目以SD雄性大鼠为模型，通过分析砷暴露下其精子组蛋白H3、H4的总甲基化和乙酰化水平及特定基因启动子的组蛋白修饰变化，表征精子表观遗传修饰的差异。通过分析选定育龄男性人群血液中砷的水平，表征砷的人群暴露特征。根据动物实验结果，分析人群精子组蛋白修饰水平的差异。最后结合临床流行病学数据和统计学方法，阐明砷暴露、组蛋白修饰和精子质量之间的相关性，从而在人群水平上验证本项目关于"砷通过改变精子的组蛋白修饰而影响其质量"的毒理学假设，并从表观遗传层面揭示砷男（雄）性生殖毒性的分子机制。

Arsenic is one of the metalloid pollutants widespread in the environment. At present, its exposure and effects on human health, especially on male reproductive health have increasingly raised public concerns. Epidemiologic researches have demonstrated that the content of arsenic in men is significantly related to the reduced sperm quality. However, its underlying molecular mechanisms were far from being completely understood. Based on the evidence that histone methylation and acetylation play a pivotal role in spermatogenesis, and that arsenic exposure can change the status of histone modifications, by using the male rat model, this proposal plans to quantify the global methylation and acetylation levels of histone H3 and H4, and investigate the histone modification changes of specific gene promoter in rat sperms. In addition, by analyzing the arsenic content in serum of reproductive-aged male population, and the histone modification status in sperms with reference to the animal experimental results, we will explore the relationships of "arsenic exposure-histone modification-sperm quality" by statistics in combination with the clinical epidemiologic data, hoping to verify our toxicological hypothesis that arsenic can affect sperm quality by altering the status of sperm histone modification on population level, and reveal the molecular mechanisms of arsenic-mediated male reproductive toxicity.