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患有遗传疾病的工人 遗传变异引起的职业暴露致突变效应的易感性 调节这种暴露的影响的蛋白质。正如最初提出的，我们已经证明了 在代谢氯乙烯(VC)的酶中遗传多态，如CYP2E1， 对VC相关生物标记物的出现有统计上显著但很小的影响 VC作业工人的突变损伤(突变型ras-p21和突变型p53)。我们还有 表明遗传多态在DNA修复中的作用要大得多 蛋白XRCC1对其中一个生物标记物(突变型p53)的出现，但对另一个没有 (突变型ras-pl1)。这些发现表明，VC诱导的诱变损伤 诱导的P53是通过XRCC1依赖的途径修复的，而VC诱导的突变 RAS中的损伤可以通过另一条途径修复。在竞争对手的这一版本中 为了继续提出建议，我们寻求对这些调查结果采取后续行动。我们建议研究 另一种常见DNA修复蛋白(XPD)的多态性试图解释这种变异性 在这些工人的mutantras-p21生物标记物中。这将通过对350VC进行基因分型来实现 XPD患者密码子312和751的检测及其与XPD检测结果的比较 包括VC暴露在内的各种因素的基因控制。我们亦建议研究 XRCC1基因多态对突变体发生影响的生物学合理性 P53生物标志物。这将通过确定这种多态对 XRCC1的结构，DNA修复过程中XRCC1与其他蛋白质的相互作用， 关于DNA修复过程中各个步骤的作用，关于VC诱导的DNA损伤的形成 DNA加合物，以及VC诱导的DNA突变在模型系统中的发生。

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.