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 originally proposed, 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-associate 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-pl 1), in these workers. These findings suggest that the VC-induced mutagenic damage induced in p53 is repaired by an XRCC 1-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 in the mutant ras-p21 biomarker in these workers. This will be accomplished by genotyping 350 VC workers for codon 312 and 751 in XPD and comparing the prevalence of the biomarker by XPD genotype controlling for various factors including VC 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 determining the effect of this polymorphism on 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 of VC-induced DNA adducts, and on the occurrence of VC-induced DNA mutations, in model systems.

Agency
National Institute of Health (NIH)
Institute
National Institute for Occupational Safety and Health (NIOSH)
Type
Research Project (R01)
Project #
2R01OH004192-04A1
Application #
6982989
Study Section
Safety and Occupational Health Study Section (SOH)
Program Officer
Newhall, Jim
Project Start
2001-07-01
Project End
2009-08-30
Budget Start
2005-08-31
Budget End
2006-08-30
Support Year
4
Fiscal Year
2005
Total Cost
$315,900
Indirect Cost
Name
Columbia University (N.Y.)
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Wang, Wei; Qiu, Yu-lan; Ji, Fang et al. (2010) Genetic polymorphisms in metabolizing enzymes and susceptibility of chromosomal damage induced by vinyl chloride monomer in a Chinese worker population. J Occup Environ Med 52:163-8

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