DNA甲基化及其关联基因突变对苯作业工人遗传损伤的调控

项目名称： DNA甲基化及其关联基因突变对苯作业工人遗传损伤的调控

项目编号： No.81472949

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 夏昭林

作者单位： 复旦大学

项目金额： 80万元

中文摘要： 苯是确定的人类致癌物。我国纯苯产量大,接触工人众多。本课题组近年研究表明，在当前职业卫生标准下，苯作业工人的微核率较对照组显著增加。最近研究证实DNA甲基化与肿瘤发生密切相关，同时DNA甲基化关联基因调控着机体DNA甲基化的发生和清除，甲基化关联基因存在大量突变，某些突变导致酶活性改变，继而引起DNA甲基化改变和影响蛋白表达，进而影响机体生命活动。本项目通过苯作业工人的接触评估,应用胞质分裂阻滞微核（CB微核)和基于CB微核的3AB指数分别检测苯作业工人外周血淋巴细胞的遗传损伤及其修复能力，确定苯致血液损害和遗传损伤的基准剂量；应用甲基化芯片绘制全基因组启动子DNA甲基化谱；应用二代测序和PCR-RFLP检测甲基化关联基因的突变位点。探讨DNA甲基化关联基因突变与甲基化的关联，并研究其对苯致遗传损伤及其修复能力的内在联系，为修订苯职业卫生标准和完善苯作业工人健康监护方案提供科学依据。

中文关键词： 苯；接触评估；遗传损伤；DNA甲基化关联基因；DNA甲基化

英文摘要： Benzene (BZ) is a well-known established human carcinogen. With huge crowd of occupationally BZ-exposed workers in China, it is of great theoretical and practical significance to seek for genetic damage and DNA repair capacity indicators for the prevention and control of BZ-induced occupational health hazard. Our previous studies have shown that BZ-exposed workers have significantly elevated MN frequencies compared with the controls under the current occupational health standard. Recent studies have confirmed that genetic damage, DNA methylation in promotor region and mutations in DNA methylation related genes are both tightly associated with leukemia. In this proposal, the cytokinesis-block micronuclei (CBMN) assay will be used to measure the genetic damage and the CBMN-based 3AB method is developed to detect the DNA repair capacity of BZ-exposed workers. Additionally, we project to perform genome-wide methylation profiling using chip technology, and detect the mutaion in DNA methylation related genes by second-generation sequencing and PCR-RFLP, seeking for the potential biomarkers. Based on exposure assesment among benzene-exposed workers, we explore the potential relationship between DNA methylation, mutaion in DNA methylation related genes and genetic damage as well as its repair capacity. This study will help to reveal the molecular mechanisms of BZ-induced genetic damage. The results from our study can be used as scientfic references in revising the BZ occupational health standard and improving occupational health surveillance program for BZ-exposed workers and other carcinogen-exposed population.

英文关键词： Benzene;Exposure assessment;Genetic damage;DNA methylation related genes;DNA methylation