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


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.
Li
Yongliang
Y
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
Marion
Marie-Jeanne
MJ
Zipprich
Jennifer
J
Freyer
Greg
G
Santella
Regina M
RM
Kanki
Chisaka
C
Brandt-Rauf
Paul W
PW
D000328:Adult; D000368:Aged; D003062:Codon / Q000235:genetics; D015331:Cohort Studies; D018736:DNA Adducts / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D011110:Polymorphism, Genetic; D014752:Vinyl Chloride / Q000378:metabolism / Q000506:poisoning*; D000076105:X-ray Repair Cross Complementing Protein 1
D003062:Codon; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D014752:Vinyl Chloride