三氯乙烯对人淋巴细胞的表观遗传效应及生物标志物的筛查

Trichloroethylene is one of the most critical occupational and environmental pollutants in China. This project, which aiming at the cutting edge technologies of epigenetics, will focus on the interactions between the environment and the organism. The human lymphocyte will be taken as the subject, and an integrated of research methods from multidisciplinary including toxicology, occupational medicine, epidemiology, Biochemistry and molecular biology ,immunology, analytical chemistry and health statistics will be applied to investigate the key scientific problem of earlier biological effect of TCE and its active mechanisms. With the help of high throughput technology the epigenetic biomarker will be screened and verified in the in vitro cultured lymphocyte system. Moreover, the relationship of epigenetic mechanisms including DNA methylation, histone modification and non-coding RNA with TCE exposure and other biological index will explored in the occupational exposure population. Based on the research above we could discover the epigenetic mechanisms in the process of TCE exposure, and screening some earlier sensitive molecular biomarker. Also, the results could provide the scientific basis for establishing early warning system and health risk assessment model. The valuable epidemiological data could be accumulated for revising the hygienic standard of TCE in future.

本项目瞄准表观遗传学研究的前沿，针对我国重要职业和环境污染物三氯乙烯健康危害的现状和工作基础，以环境与机体交互作用为核心，综合运用毒理学、职业医学、流行病学、生物化学与分子生物学、免疫学、分析化学、卫生统计学等多学科手段，以人类淋巴细胞为研究对象，研究我国TCE早期生物效应及其作用机制这一关键科学问题。应用高通量的芯片技术，通过淋巴细胞体外培养，筛查并验证关键的表观遗传表征，进一步应用于职业接触人群，重点探讨表观遗传调控机制即DNA甲基化、组蛋白修饰和非编码RNA与ＴＣＥ暴露（环境监测和体内负荷）和其他其他生物效应指标（生化、免疫、遗传）及可能存在的重要健康损害的关系；揭示ＴＣＥ暴露过程中的表观遗传学变化的规律，筛查早期敏感的分子生物标志物，为建立预警体系和健康危险度评价的新模式以及有效的干预措施提供科学依据。为我国未来修订ＴＣＥ卫生标准提供人群流行病学资料。

项目瞄准表观遗传学研究的前沿,针对我国重要职业和环境污染物三氯乙烯健康危害的现状和工作基础,以环境与机体交互作用为核心,以人类淋巴细胞为研究对象,研究TCE早期生物效应及其作用机制这一关键科学问题。通过体外研究、人群调查、动物实验三种研究模式,全面地对TCE对淋巴细胞生物学效应进行了系统探讨, 结果显示,TCE暴露可以影响T细胞分化, 主要表现为低剂量染毒促进初始T细胞向是Th2和Treg方向分化，随着TCE剂量增加和作用时间延长，促进初始T细胞向Th17分化，同时血清中相关细胞因子也发生相应变化；表观遗传指标检测发现TCE可以引起淋巴细胞microRNA和DNA甲基化模式发生改变,差异表达的microRNA和DNA甲基化模式的下游调控基因多集中在与T细胞分化和T细胞介导的免疫功能相关的信号通路中,进一步的验证工作也证明了其相关性,但相关的调控机制尚需进一步探讨和明确。