Title: Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water.
Authors: Andrew, Angeline S; Karagas, Margaret R; Hamilton, Joshua W
Published In Int J Cancer, (2003 Apr 10)
Abstract: Arsenic is well established as a human carcinogen, but its precise mechanism of action remains unknown. Arsenic does not directly damage DNA, but may act as a carcinogen through inhibition of DNA repair mechanisms, leading indirectly to increased mutations from other DNA damaging agents. The molecular mechanism underlying arsenic inhibition of nucleotide excision repair after UV irradiation (Hartwig et al., Carcinogenesis 1997;18:399-405) is unknown, but could be due to decreased expression of critical genes involved in nucleotide excision repair of damaged DNA. This hypothesis was tested by analyzing expression of repair genes and arsenic exposure in a subset of 16 individuals enrolled in a population based case-control study investigating arsenic exposure and cancer risk in New Hampshire. Toenail arsenic levels were inversely correlated with expression of critical members of the nucleotide excision repair complex, ERCC1 (r(2) = 0.82, p < 0.0001), XPF (r(2) = 0.56, p < 0.002), and XPB (r(2) = 0.75, p < 0.0001). The internal dose marker, toenail arsenic level, was more strongly associated with changes in expression of these genes than drinking water arsenic concentration. Our findings, based on human exposure to arsenic in a US population, show an association between biomarkers of arsenic exposure and expression of DNA repair genes. Although our findings need verification in a larger study group, they are consistent with the hypothesis that inhibition of DNA repair capacity is a potential mechanism for the co-carcinogenic activity of arsenic.
PubMed ID: 12569548
MeSH Terms: Adult; Aged; Arsenic Poisoning/epidemiology; Arsenic Poisoning/genetics*; Arsenic/adverse effects*; Arsenic/analysis; Biomarkers, Tumor/genetics*; Biomarkers, Tumor/metabolism; Case-Control Studies; DNA Helicases; DNA Repair/genetics*; DNA, Neoplasm/genetics*; DNA, Neoplasm/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Down-Regulation; Endonucleases; Female; Gene Expression; Humans; Male; Middle Aged; Nails/chemistry; New Hampshire/epidemiology; Nuclear Proteins; RNA, Messenger/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Transcription Factors; Urinary Bladder Neoplasms/epidemiology; Urinary Bladder Neoplasms/genetics*; Water Pollution, Chemical/adverse effects; Water Pollution, Chemical/analysis; Water Supply/analysis; X-ray Repair Cross Complementing Protein 1; Xeroderma Pigmentosum Group A Protein