代谢和组蛋白修饰共调控在砷暴露致学习记忆障碍中的作用机制研究

砷是环境中广泛存在的一种类金属污染物，其人群暴露对神经系统的影响已引起了人们的广泛关注。学习记忆能力是中枢神经系统功能的重要方面。研究表明，砷可影响学习记忆关键基因的表达，从而损害大脑学习记忆能力，但其影响基因表达的分子机制并不完全清楚。基于组蛋白修饰与学习记忆功能的密切关系，以及砷甲基化代谢和机体代谢对组蛋白修饰的调控作用，本项目拟针对儿童这一易感性群体，以幼年大鼠为研究对象，分析砷在脑组织中的代谢特征，以及砷暴露对皮质、海马的代谢和组蛋白甲基化/乙酰化修饰的影响，并在细胞水平上加以验证。希望证明砷可通过自身代谢及干扰脑组织代谢改变皮质、海马的组蛋白修饰水平，进而影响学习记忆相关基因表达，最终损害大脑学习记忆能力的毒理学假设。本项目研究结果有助于阐明“砷甲基化-脑组织代谢-组蛋白修饰”共调控在砷暴露致学习记忆障碍中的耦合作用机制，从表观遗传层面深入揭示砷诱导神经毒性的分子机理。

Arsenic is a kind of metalloid pollutant widespread in the environment, and the influence of its exposure on nervous system has raised great public concerns. Learning and memory are the important aspects of central nervous system function. Previous studies have shown that arsenic can affect the expression of key genes involved in learning and memory, thus impairing the ability of brain learning and memory. However, the molecular mechanism of its regulation on gene expression is still unclear. Based on the close relationship between histone modification and learning and memory function, and the regulation of arsenic methylation metabolism and body metabolism on histone modifications, by using the young rats as animal models, this project aims to analyze the metabolic characteristics of arsenic in brain tissue, and the effects of arsenic exposure on metabolism as well as histone methylation/acetylation status in rat cortex and hippocampus. The animal experimental results will be further verified on cell models. Through doing these, it is hoped to validate our toxicological hypothesis that arsenic can change the level of histone modification in cortex and hippocampus by self-methylation and disturbing brain metabolism, thereby affecting the expression of learning and memory-related genes, and ultimately leading to learning and memory dysfunction. The results of this project will help to elucidate the coupled role of "arsenic methylation-brain metabolism-histone modification" co-regulation in learning and memory impairment induced by arsenic exposure, and to deeply reveal the epigenetic mechanisms of arsenic-induced neurotoxicity.