砷急性暴露诱导的氧化应激与DNA甲基化异常的关联作用研究

Arsenic is a known toxin and carcinogen of the environment pollutants. It is present in industrial settings and in the pollutional water and soil. Exposure to high concentrations of arsenic is associated several cancers. The mechanisms by which arsenic causes human cancers are not well understood. The oxidative stress and abnormal DNA methylation were reported the two important potential carcinogenic actions for arsenic. Our research found that arsenite induced oxidative stress and G2/M cell cycle arrest, the results first time showed that DNA methylation change was involved in regulation of arsenite induced G2/M cell cycle arrest. This finding provides a good cell model to analysis the interaction of arsenic induced oxidation stress and DNA methylation change. The finding also suggested that the process of arsenite induced DNA methylation change regulating cell cycle arrest may involve in arsenite induced tumorigeness, and the target gene of DNA methylation deserved to be further researched. In this research, it is plan to use the cell cycle arrest model, use the technique of DNA methylation array and gene array, and following the DNA methylation sequencing and Real time-PCR verification to identify the mechanism and the target of DNA methylation in arsenite induced cell cycle arrest, and to investigate the relationship between oxidation stress and DNA methylation, two tumorigeness mechanisms of arsenite. The accomplishment of the research plan is useful to further understand the tumorigeness mechanism of arsenic, and is useful to cure and prevent the tumorigeness in the case of exposure to high concentrations of arsenic.

砷作为环境污染物中的毒素和致癌物，其高剂量暴露与多种癌症发生有关，其详细致癌机制仍不明确。氧化应激和基因组甲基化异常是砷的两种潜在致癌机制。本课题前期研究表明，砷诱导的氧化应激能引起细胞周期阻滞，并首次发现DNA甲基化参与调控细胞周期阻滞。这一发现为研究砷诱导的氧化应激与DNA甲基化异常间的关联提供了理想细胞模型。此发现也提示，DNA甲基化调控细胞周期过程可能是砷诱导肿瘤发生的重要事件，其具体作用靶点值得深入研究。本研究计划利用砷诱导的细胞周期阻滞模型，通过DNA甲基化芯片和基因芯片分析，结合亚硫酸氢盐测序、Real-time PCR等验证方法，明确DNA甲基化调控细胞周期的机制与作用靶点，并确认砷诱导的氧化应激是否调控DNA甲基化模式变化，初步探讨砷毒性背景下两种致癌机制的关系。本研究的完成有利于深入理解砷的致癌机制，对治疗和预防砷职业或意外暴露引发的人体损伤和癌症有重要意义。