Worker Genetic Susceptibility to Mutagenic Risk

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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.