Worker Genetic Susceptibility to Mutagenic Risk

描述（由申请人提供）：假设工人的基因型和工作场所的危险暴露之间的基因-环境相互作用对于识别那些处于职业病最高风险的工人以及针对潜在的干预措施以降低风险和预防疾病是重要的。一个可能的模型系统，研究这种范式在职业致癌作用是由工人暴露于致癌物质氯乙烯（VC）和风险的发展血管瘤的肝脏（ASL）。VC代谢（通过CYP 2 E1）转化为反应性中间体，生成可通过碱基切除修复去除的前致突变乙烯基-DNA加合物（通过XRCC 1）或核苷酸切除修复（通过XPD），或者，如果没有修复，导致癌症相关基因的特定突变（ras癌基因和TP 53肿瘤抑制基因），在暴露工人中作为循环突变蛋白生物标志物可检测到（分别为突变型ras-p21蛋白和突变型p53蛋白或突变型p53蛋白的自身抗体）。我们的流行病学研究VC工人的日期表明，在几个基因（CYP 2 E1，XRCC 1和XPD）的遗传多态性和这些生物标志物的获得性遗传损伤的发生独立的累积VC暴露之间的统计学显着的关联。迄今为止的实验研究已经为CYP 2 E1和XRCC 1多态性的这种影响提供了生物学上的可接受性，但最大的遗传归因风险似乎是由于XPD多态性。因此，这一修订后的竞争性延续提案的目的是使用一系列实验性计算机模拟、体外和体内方法，证明XPD多态性对VC诱导的遗传损伤易感性的相似生物相容性。一旦工人被确定为高风险，由于他们的遗传或获得性遗传缺陷，针对这些特定缺陷的干预措施可以在未来的研究中治疗或预防由此产生的癌症。由于VC是世界上产量最高的化学品之一，有大量工人接触，因此研究这一经济主要制造部门工人的健康影响是NIOSH国家职业研究议程的重要目标。此外，由于这些相同的途径参与了许多其他工作场所化学品造成的遗传损伤，这项研究可能对工作场所的基因-环境相互作用/干预具有更广泛的意义。

DESCRIPTION (provided by applicant): Gene-environment interactions between workers' genotypes and hazardous exposures in the workplace are hypothesized to be important for identifying those workers at the highest risk for developing occupational diseases and for targeting potential interventions to reduce that risk and prevent disease. A possible model system for studying this paradigm in occupational carcinogenesis is provided by workers exposed to the carcinogen vinyl chloride (VC) and at risk for the development of angiosarcomas of the liver (ASLs). VC is metabolized (by CYP2E1) to reactive intermediates that generate pro-mutagenic etheno-DNA adducts that can be removed by base excision repair (via XRCC1) or nucleotide excision repair (via XPD), or, if not repaired, result in specific mutations in cancer-related genes (the ras oncogene and the TP53 tumor suppressor gene) that are detectable as circulating mutant protein biomarkers in exposed workers (mutant ras-p21 protein and mutant p53 protein or autoantibodies to mutant p53 protein, respectively). Our epidemiologic studies to date of VC workers demonstrate a statistically significant association between inherited polymorphisms in several genes (CYP2E1, XRCC1 and XPD) and the occurrence of these biomarkers of acquired genetic damage independent of cumulative VC exposure. Experimental studies to date have provided the biological plausibility for this effect of polymorphisms in CYP2E1 and XRCC1, but the largest genetic attributable risk appears to be due to XPD polymorphisms. Thus, the aim of this revised competing continuation proposal is to demonstrate similar biological plausibility for polymorphisms in XPD on susceptibility to VC-induced genetic damage using an array of experimental in silico, in vitro and in vivo approaches. Once workers are identified as high-risk due to their inherited or acquired genetic defects, interventions targeted at these specific defects can be developed to treat or prevent the resultant cancers in future studies. Since VC is one of the highest production volume chemicals in the world with large numbers of workers exposed, study of the health effects of workers in this major manufacturing sector of the economy are an important target for study under the NIOSH National Occupational Research Agenda. Furthermore, since these same pathways are involved in the genetic damage due to many other workplace chemicals, this study could have wider significance for gene-environment interactions/interventions in the workplace generally.