1,3-丁二烯（BD）是重要环境污染物和确定人类致癌物。前期研究发现BD职业接触人群遗传损伤指标核质桥（NPB）率显著升高，但BD诱导NPB形成的机制不明。前期研究及NPB形成方式提示，BD诱导的NPB来源于DNA双链断裂后的DNA重组修复过程。最新报道表明BD可引起显著的DNA甲基化改变，由于甲基化修饰是DNA重组修复系统基因表达调控的重要机制，由此提出：BD通过对DNA重组修复系统关键基因的甲基化调控，引起该系统功能异常，使BD所致的DNA双链断裂倾向于发生易错修复，导致NPB过多生成。项目拟在确定BD诱导NPB形成的动力学过程基础上，揭示DNA重组修复系统关键基因在BD致NPB形成中的甲基化调控机制，进一步在职业接触人群中验证BD接触与遗传损伤和表观遗传损伤的反应关系。综合分析阐明BD诱导NPB形成的DNA甲基化作用机制。为深入阐释BD遗传毒性机理提供科学依据。

1,3-butadiene(BD) is an important environmental pollutant and industrial chemical with occupationally exposed subjects worldwidely. It was classified as a human carcinogen in 2007 by the International Agency for Research on Cancer. So it is critical to verify the biomarkers which can reflect the harmful effects of BD in exposed populations to prevent the BD-related cancer. Our previous study in China showed that the frequency of nucleoplasmic bridge (NPB) increased significantly in BD-exposed workers when compared with the subjects in control group, suggesting that NPB may be a sensitive indicator for the genetic damage induced by BD. However the progress and molecular mechanisms underlying the formation of NPB induced by BD has not been elucidated. Our previous results also displayed that the frequcies of micronucleus and NPB increased simultaneously in BD-exposed group, and there were positive relationship between these genotoxic indexes. Combined with the theory of NPB origin, it can be concluded that BD induces NPB by causing the DNA double strands breaks and DNA recombination repair system should play an important role in the progress of NPB formation. On the other hand,the latest report showed that BD was also an epigenetic toxicant with extensive demethylation on global DNA and DNA repetitive elements in mice after short-term inhalational exposure to low dose of BD. Since DNA methylation modification is one of the important mechanisms of expressional regulation for genes in DNA recombination systems, the following scientific hypothesis can be acquired: BD may cause the dysregulation of genes in DNA recombination systems by inducing DNA methylation modification, then DNA double strands breaks indcued by BD is prone to be repaired by the way of non-homologouse end-joining, which will lead to the extra formation of NPB. Based on the hypothesis, this research is planned to verify the dynamic progress from DNA double strands breaks to formation of NPB induced by BD firstly. Then in vitro and in vivo tests will be conducted to screen the target genes in DNA recombination system which are dysregulated by the way of DNA methylation modification, and to verify the effects on the formation of NPB induced by BD. Finally epidemiologic study will conducted to clarify the relationship between BD exposure with genetic damage and epigenetic damage in BD occupationally exposed workers in China. This research will be helpful to explain the molecular mechanisms of genotoxicity induced by BD, and to provide the evidence of NPB as a sensitive indicator of reflecting the genetic damage in BD-exposed populations.