Vinyl chloride (VC) is a widespread environmental contaminant, and a known carcinogen in humans. Preliminary data suggest that some workers exposed to VC have persistent elevated mutant frequencies in their peripheral blood lymphocytes, and that others do not . This leads to a hypothesis that there may be genetic differences in susceptibility to VC-induced change. We postulate that either xenobiotic metabolism r DNA repair are responsible for such differential susceptibility. The major goal of this project is to utilize biomarkers of exposure and effect to test these hypotheses. We will collect and store samples, analyze questionnaires and computerize data for a final population of more than 410 individuals that have been occupationally exposed to VC. Blood samples will be processed for analysis of various biomarkers of VC-induced genetic damage. Mutant frequencies at the X-linked hypoxanthine guanine phosphoribosyl transferase (hprt) locus in peripheral T lymphocytes will be determined and the molecular nature of the T-cell receptor gene locus will be analyzed to determine the degree of clonality among observed mutants. These data will allow determination of the actual mutation frequency in each subject. As an independent measure of induced mutation, the frequencies of glycophorin A (GPA) variants in red blood cells will be determined in samples from the same individuals. The molecular nature of the hprt mutants will be analyzed by multiplex PCR and sequencing to determine if there are """"""""signature"""""""" mutations induced by vinyl chloride exposures in vivo. Differential susceptibility could be due to variable capacity to metabolize vinyl chloride. Recently, RFLPs have been defined for the cytochrome P-450 CYP2E1 that appear to be associated with different levels of transcriptional activity. Studies will determine whether these RFLPs are associated with high or low mutant frequencies in the exposed workers. Polymorphisms in glutathione-S-transferase mu and the uninvolved P450 species CYP1A1 also will be examined. An alternative to metabolism as a cause for differential susceptibility is DNA repair. Up to ten highly exposed individuals with high mutation frequencies, and ten highly exposed individuals with normal mutation frequencies will be identified. B-lymphoblastoid cell lines, already prepared from these individuals , as well as the original lymphocyte samples, will be examined for DNA repair capacity by (i) measuring the rate of adduct loss after exposure to the VC metabolite CEO (ii) screening for N-methylpurine-DNA glycosylase expression and (iii) determining cell cycle checkpoint response. Representative lines also will be tested for susceptibility to CEO-induced hpri mutation. These studies will determine whether susceptibility to mutation seen in vivo is maintained in the transformed B- cell lines as a consequence of variation in DNA repair or cell cycle checkpoint response. The presence of one particular mutated p21 ras protein - with aspartic acid at codon 13 instead of glycine (Asp13p21 ras) will be monitored in the serum of individuals exposed to VC. The goal of this study is to evaluate whether the presence of this mutated protein is (i) a predictor of individuals with high mutation frequencies, (ii) a predictor of those at high risk for developing a liver angiosarcoma (ASL), and (iii) an early marker of the onset of ASL.

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