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The role of XRCC1 polymorphisms in base excision repair of etheno-DNA adducts in French vinyl chloride workers.

Li-Y; Marion-M-J; Zipprich-J; Freyer-G; Santella-R; Kanki-C; Brandt-Rauf-P

Int J Occup Med Environ Health 2006 Jan/Mar; 19(1):45-52

http://dx.doi.org/10.2478/v10001-006-0006-9

20042197

OBJECTIVES: The purpose of this study was to examine whether polymorphisms in the XRCC1 DNA-repair protein can affect the base excision repair capacity to remove etheno-DNA adducts induced by vinyl chloride exposure that account for the occurrence of mutant biomarkers of effect seen in exposed workers. MATERIALS AND METHODS: Using polymerase chain reaction-restriction fragment length polymorphism and fluorescence polarization techniques, we examined the effect of three x-ray cross complementing-1 protein polymorphisms, at codons 194, 280 and 399, on the occurrence of mutant biomarkers in ras-p21 and p53 induced by vinyl chloride exposure in a cohort of 211 French vinyl chloride workers to correlate differences in genotype with differences in the presence of these biomarkers. Also, cell cultures of lymphoblast lines from a pair of individuals, one homozygous wild-type and one homozygous variant for the codon 399 polymorphism, were exposed to the reactive intermediate of vinyl chloride, and, using an enzyme-linked immunosorbent assay, levels of etheno-DNA adducts generated and repaired were measured and compared. RESULTS: After adjusting for age, smoking, alcohol drinking and cumulative vinyl chloride exposure, compared to workers who were homozygous wild-type for all alleles, the odds ratio for the presence of either biomarker increased to 2.0 (95% CI: 1.0-3.9) for workers with any one variant allele and to 2.4 (95% CI: 1.1-5.2) for workers with more than one variant allele. Data from the cell culture experiments indicating that repair of etheno-DNA adducts is considerably better in wild-type cells compared to polymorphic cells were supportive of the epidemiologic results. CONCLUSIONS: This study provides further evidence that polymorphisms in XRCC1 can be an important biomarker of susceptibility in populations exposed to agents that produce damage removed by base excision repair.

Proteins; Biomarkers; Mutation; Mutagens; Exposure-levels; Workers; Work-environment; Enzymatic-effects; Enzymes; Cellular-function; Epidemiology; Author Keywords: Base excision repair; DNA adducts; Mutations; Gene-environment interaction

Prof. P.W. Brandt-Rauf, Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Avenue, New York, NY 10032

IOMHEZ

75-01-4

20060101

Journal Article

pwb1@columbia.edu

Grant

2006

Grant-Number-R01-OH-004192

1

0867-8383

International Journal of Occupational Medicine and Environmental Health

NY

Department of Environmental Health Sciences, The Mailman School of Public Health, Columbia University, New York, New York