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.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1996
Total Cost
Indirect Cost
Balik-Meisner, Michele; Truong, Lisa; Scholl, Elizabeth H et al. (2018) Elucidating Gene-by-Environment Interactions Associated with Differential Susceptibility to Chemical Exposure. Environ Health Perspect 126:067010
To, Kimberly T; Fry, Rebecca C; Reif, David M (2018) Characterizing the effects of missing data and evaluating imputation methods for chemical prioritization applications using ToxPi. BioData Min 11:10
Dalaijamts, Chimeddulam; Cichocki, Joseph A; Luo, Yu-Syuan et al. (2018) Incorporation of the glutathione conjugation pathway in an updated physiologically-based pharmacokinetic model for perchloroethylene in mice. Toxicol Appl Pharmacol 352:142-152
Gray, Kathleen M (2018) From Content Knowledge to Community Change: A Review of Representations of Environmental Health Literacy. Int J Environ Res Public Health 15:
Li, Gen; Jima, Dereje; Wright, Fred A et al. (2018) HT-eQTL: integrative expression quantitative trait loci analysis in a large number of human tissues. BMC Bioinformatics 19:95
Adebambo, Oluwadamilare A; Shea, Damian; Fry, Rebecca C (2018) Cadmium disrupts signaling of the hypoxia-inducible (HIF) and transforming growth factor (TGF-?) pathways in placental JEG-3 trophoblast cells via reactive oxygen species. Toxicol Appl Pharmacol 342:108-115
Smeester, Lisa; Fry, Rebecca C (2018) Long-Term Health Effects and Underlying Biological Mechanisms of Developmental Exposure to Arsenic. Curr Environ Health Rep 5:134-144
Luo, Yu-Syuan; Furuya, Shinji; Chiu, Weihsueh et al. (2018) Characterization of inter-tissue and inter-strain variability of TCE glutathione conjugation metabolites DCVG, DCVC, and NAcDCVC in the mouse. J Toxicol Environ Health A 81:37-52
Singleton, David R; Lee, Janice; Dickey, Allison N et al. (2018) Polyphasic characterization of four soil-derived phenanthrene-degrading Acidovorax strains and proposal of Acidovorax carolinensis sp. nov. Syst Appl Microbiol 41:460-472
Luo, Yu-Syuan; Hsieh, Nan-Hung; Soldatow, Valerie Y et al. (2018) Comparative analysis of metabolism of trichloroethylene and tetrachloroethylene among mouse tissues and strains. Toxicology 409:33-43

Showing the most recent 10 out of 505 publications