Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water

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.

Aristolochic acid suppresses DNA repair and triggers oxidative DNA damage in human kidney proximal tubular cells

“…Similar findings were reported by Cheng et al (59) and Wei et al (60) they found that low mRNA levels of DNA-repair genes (including ERCCC1 and ERCC2) in lymphocytes were associated with high relative risk for head and neck cancer and lung cancer. The decreased expression of ERCC1 by AA treatment is also in accordance to the study in which arsenic can diminish the expression of the nucleotide excision repair genes ERCC1, XPF (ERCC4), and XPB (ERCC3) (61). Another DNA repair gene, MGMT (O-6-methylguanine-DNA methyltransferase), was downregulated in 30 μM AA treatment but this result is opposite to that in AA-treated rats (44).…”

Genomic and Proteomic Profiling of Responses to Toxic Metals in Human Lung Cells

“…For example, the following DNA repair genes were altered after arsenic treatment: Xeroderma pigmentosum group D-complementing protein (XPD, DNA excision repair protein ERCC2), Xeroderma pigmentosum group C-complementing protein (XPC), AP endonuclease 1 (APE1), DNA ligase-1 (DNL1), DNA polymerase delta catalytic subunit (DPD), DNA topoisomerase II alpha (TOP2A), DNA damage-inducible protein GADD45 (Chen et al 2000;Liu et al 2001 replication licensing factors 2 and 7 (MCM2, MCM7), proliferating cyclic nuclear antigen (PCNA), O 6 -methylguanine-DNA methyltransferase (MGMT), replication factor C large and 40-kDa subunits (RFC, RFC40), and uracil-DNA glycosylase precursor (UNG1). Other studies in our laboratory using human lymphocytes from an epidemiologic study have demonstrated a dose-dependent correlation between decreased expression of nucleotide excision repair genes and chronic exposure to arsenic in the drinking water (Andrew et al 2003). Surprisingly, increasing the dose of arsenic to 50 µM did not simply increase the magnitude of the change in the same set of genes or add additional genes.…”

Role of glucocorticoid receptor in acclimation of killifish (Fundulus heteroclitus) to seawater and effects of arsenic

“…For example, inorganic arsenic alone has been consistently negative for carcinogenesis in animal bioassays, but arsenic in drinking water greatly enhances the tumorigenicity of ultraviolet radiation in a mouse model (33). Similar synergistic or potentiating effects of arsenic have been seen for endocrine disruption (6,16), angiogenesis (17,38), and DNA damage and repair (3,13). Human epidemiology studies also have shown that arsenic is strongly synergistic with cigarette smoking for risk of lung cancer (10,37).…”