Worker Genetic Susceptibility to Mutagenic Risk

面临工作场所相关健康影响风险的特殊人群包括因介导职业暴露影响的蛋白质遗传变异而对职业暴露诱变影响具有遗传易感性的工人。正如最初提出的，我们已经证明，遗传多态性的代谢氯乙烯（VC）的酶，如CYP 2 E1，有一个统计学上显着的，但很小的影响发生的生物标志物的VC相关的诱变损伤（突变ras-p2 l和突变p53）在VC暴露工人。我们还证明了DNA修复蛋白XRCC 1中的遗传多态性对这些工人中其中一种生物标志物（突变型p53）的出现有更大的显着影响，但对另一种生物标志物（突变型ras-p11）的出现没有影响。这些结果表明，VC诱导的突变损伤诱导的p53是修复的XRCC 1依赖性途径，但VC诱导的突变损伤ras可能是修复的替代途径。在对一项竞争性延续建议的修订中，我们力求对这些调查结果采取后续行动。我们建议检查另一种常见的DNA修复蛋白（XPD）的多态性，试图解释这些工人突变ras-p21生物标志物的变异性。这将通过对350名VC工作者进行XPD中密码子312和751的基因分型，并通过控制包括VC暴露在内的各种因素的XPD基因型比较生物标志物的患病率来实现。我们还建议检查XRCC 1多态性对突变型p53生物标志物发生的影响的生物相容性。这将通过确定这种多态性对XRCC 1结构的影响，对XRCC 1和DNA修复过程中其他蛋白质之间的相互作用，对DNA修复过程中各个步骤的功能，对VC诱导的DNA加合物的形成，以及对模型系统中VC诱导的DNA突变的发生来实现。

Special populations at risk for workplace-related health effects include workers with genetic susceptibility to the mutagenic effects of occupational exposures due to inherited variations in the proteins that mediate the effects of such exposures. As originally proposed, we have demonstrated that inherited polymorphisms in enzymes that metabolize vinyl chloride (VC), such as CYP2E1, have a statistically significant, but small, effect on the occurrence of biomarkers of VC-associate mutagenic damage (mutant ras-p2l and mutant p53) in VC-exposed workers. We have also demonstrated a much larger significant effect of an inherited polymorphism in the DNA repair protein XRCC1 on the occurrence of one of these biomarkers (mutant p53), but not the other one (mutant ras-pl 1), in these workers. These findings suggest that the VC-induced mutagenic damage induced in p53 is repaired by an XRCC 1-dependent pathway but that the VC-induced mutagenic damage in ras may be repaired by an alternate pathway. In this revision of a competing continuation proposal, we seek to follow-up on these findings. We propose to examine polymorphisms in another common DNA repair protein (XPD) to attempt to explain the variability in the mutant ras-p21 biomarker in these workers. This will be accomplished by genotyping 350 VC workers for codon 312 and 751 in XPD and comparing the prevalence of the biomarker by XPD genotype controlling for various factors including VC exposure. We also propose to examine the biological plausibility for the effect of the XRCC1 polymorphism on the occurrence of the mutant p53 biomarker. This will be accomplished by determining the effect of this polymorphism on the structure of XRCC1, on interactions between XRCC1 and other proteins in the DNA repair process, on the functioning of the various steps in the DNA repair process, on the formation of VC-induced DNA adducts, and on the occurrence of VC-induced DNA mutations, in model systems.