Worker Genetic Susceptibility to Mutagenic Risk

描述(由申请人提供)：假定工人的基因-环境相互作用对于确定哪些工人罹患职业病的风险最高，并针对潜在的干预措施以降低风险和预防疾病具有重要意义。接触致癌物氯乙烯(VC)并有患肝脏血管肉瘤(ASLS)风险的工人提供了一种可能的模型系统，用于研究职业致癌中的这一范式。VC被代谢成活性中间体，产生促突变的亚甲基DNA加合物，这些加合物可以通过碱基切除修复(通过XRCC1)或核苷酸切除修复(通过XPD)移除，或者，如果不修复，会导致癌症相关基因(ras癌基因和TP53抑癌基因)的特定突变，这些突变可以作为接触者循环突变蛋白生物标记物检测到(分别是突变的ras-p21蛋白和突变的p53蛋白或突变的p53蛋白的自身抗体)。到目前为止，我们对VC工作者的流行病学研究表明，几个基因(CYP2E1、XRCC1和XPD)的遗传多态与这些获得性遗传损伤的生物标记物的出现之间存在统计学上的显著关联，这些生物标志物独立于累积的VC暴露。到目前为止，实验研究已经为这种影响提供了生物学上的可能性，但最大的遗传归因风险似乎是由于XPD基因的多态。因此，这项修订后的竞争性延续方案的目的是利用一系列在计算机、体外和体内的实验方法，证明XPD的多态对VC诱导的遗传损伤的易感性具有类似的生物学合理性。一旦工人因遗传或后天遗传缺陷而被确定为高危人群，就可以开发针对这些特定缺陷的干预措施，以在未来的研究中治疗或预防由此产生的癌症。由于VC是世界上产量最大的化学品之一，暴露了大量工人，因此研究这一主要制造业经济部门工人的健康影响是NIOSH国家职业研究议程下的一个重要研究目标。此外，由于这些相同的途径涉及许多其他工作场所化学品造成的遗传损害，这项研究可能对工作场所一般的基因-环境相互作用/干预具有更广泛的意义。 公共卫生相关性：这项提案具有重大的公共卫生相关性，因为美国数以万计的工人和全球数百万工人可能接触到致癌物质氯乙烯。这项修订后的竞争继续提案的目标是记录DNA核苷酸切除修复途径中的遗传因素，这些遗传因素对于调节工人与增加他们癌症风险的致癌暴露之间的相互作用至关重要。这不仅关系到改善接触氯乙烯的工人的健康，而且也关系到一系列行业的工人，因为接触到许多其他工作场所毒素时也会发生类似的相互作用。

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. PUBLIC HEALTH RELEVANCE: This proposal has significant Public Health Relevance because tens of thousands of workers in the U.S. and millions of workers worldwide are potentially exposed to the carcinogen vinyl chloride. The goal of this revised competing continuation proposal is to document genetic factors in DNA nucleotide excision repair pathways that are critical for mediating the interaction between the workers and this carcinogenic exposure that increase their risk of cancer. This has relevance not only for improving the health of workers exposed to vinyl chloride but also for workers in a range of industries because similar interactions occur with exposures to a host of other workplace toxins.