Worker Genetic Susceptibility to Mutagenic Risk

有工作场所相关健康影响风险的特殊人群包括具有遗传病的工人。 由于遗传变异，对职业暴露的诱变效应的敏感性 介导这种暴露效应的蛋白质。正如最初提出的，我们已经证明， 遗传了代谢氯乙烯（VC）的酶的多态性，如CYP 2 E1， 对VC相关的生物标志物的发生具有统计学显著性，但影响很小。 突变损伤（突变型ras-p2 l和突变型p53）在VC暴露工人。我们还 证明了遗传多态性在DNA修复中的更大的显着影响， 蛋白XRCC 1对这些生物标志物之一（突变型p53）的发生起作用，但对另一种生物标志物不起作用 （突变型ras-pl 1）。这些发现表明VC诱导的突变损伤 在p53中诱导的突变通过XRCC 1依赖性途径修复，但VC诱导的突变 RAS中的损伤可以通过替代途径修复。在这一修订版的竞争 我们会继续跟进这些调查结果。我们建议研究 另一种常见的DNA修复蛋白（XPD）的多态性，试图解释变异性 突变型p21生物标志物中。这将通过对350 VC进行基因分型来完成 XPD中密码子312和751的工作者，并通过XPD比较生物标志物的患病率 基因型控制各种因素，包括VC暴露。我们亦建议研究 XRCC 1多态性对突变体发生影响的生物学可解释性 p53生物标志物。这将通过确定这种多晶型对 XRCC 1的结构，XRCC 1与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 模型系统中DNA加合物以及VC诱导的DNA突变的发生。

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 originallyproposed, 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-associated 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-pl1),in these workers. These findings.suggestthat the VC-inducedmutagenic damage induced in p53 is repaired by an XRCC1-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 inthe mutantras-p21 biomarker inthese workers. This will be accomplished by genotyping 350VC workers for codon 312 and 751 in XPD and comparing the prevalence of the biomarker by XPD genotype controlling for various factors includingVC 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 determiningthe effect of this polymorphismon 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 ofVC-induced DNA adducts, and on the occurrence of VC-induced DNA mutations, in model systems.