Although the epidemiological evidence linking arsenic exposure with increased cancer risk is strong, attempts to induce carcinomas in animals have generally failed. This has hindered mechanistic studies of arsenic carcinogenesis. We previously found that low concentrations of arsenite are not mutagenic, but act as comutagens, most likely due to inhibition of DNA repair (both base and nucleotide excision repair). However, in biochemical assays, no specific repair enzyme has been found to be sensitive to low concentrations of arsenite, leading to the hypothesis that the effects of arsenite on DNA repair may result from faulty DNA damage-inducible signaling which controls DNA repair. In a test of this hypothesis, we recently showed that in cells treated with 0.1?M arsenite and ionizing radiation, the p53-dependent increase in p21 expression, normally a block to cell cycle progression after DNA damage, is deficient. In addition, arsenite treatment increased cyclin D1 abundance. To determine if arsenite acts as an enhancing agent (cocarcinogen) with a genotoxic partner, we chose solar UVR to induce skin cancer in hairless Skh1 mice. Mice given 10 mg/l sodium arsenite in drinking water for 26 weeks had a 2.4-fold increase in tumor yield after 1.7 KJ/m2 UVR 3 times weekly compared with mice given UVR alone. In a second experiment, we found a dose-related cocarcinogenic effect with a peak enhancement (almost 5-fold) at 5 mg/l arsenite + 1.0 KJ/m2 UVR. The tumors were mostly squamous cell carcinomas, and those occurring in mice given UVR plus arsenite appeared earlier and were much larger and more invasive than in mice given UVR alone. Normal skin obtained at the end of the experiment showed an increased epidermal thickness and an increased fraction of epidermal cells expressing proliferating cell nuclear antigen (PCNA) in mice exposed to arsenite compared with control mice. In mice exposed to arsenite plus UVR there was a synergistic effect on proliferation. However, the increased proliferation was already apparent at the lowest arsenite dose used (1.25 mg/l) and did not increase at higher doses. These results are consistent with the hypothesis that arsenite acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and increasing proliferation. In addition, our data suggests that arsenite-induced increases in epithelial cell proliferation might be a necessary, but not a sufficient, cause of cocarcinogenisis with UVR, since increased proliferation alone does not lead to skin cancer and does not correlate with cocarcinogenesis. Another area of study involves identification of possible biomarkers of genetic susceptibility to arsenic toxicity and carcinogenicity. Human lymphoblast lines from different normal unexposed donors showed variable sensitivities to the toxic effects of arsenite. We used microarray analysis to compare the basal gene expression profiles between two arsenite-resistant (GMO02707, GMO00893A) and two arsenite-sensitive lymphoblast lines (GMO00546B, GMO00607C). A number of genes were differentially expressed in arsenite-sensitive and arsenite-resistant cells. Among these, ?-glutamyltranspeptidase 1 (GGT1) showed higher expression levels in arsenite-resistant cells. RT-PCR analysis with gene-specific primers confirmed these results. Reduction of GGT1 expression level in arsenite resistant lymphoblasts with GGT1-specific siRNA resulted in increased cell sensitivity to arsenite. In conclusion, we have demonstrated for the first time that expression levels of GGT1 might useful as a biomarker of genetic susceptibility to arsenite.