Arsenite is a cocarcinogen with solar ultraviolet radiation for mouse skin: An animal model for arsenic carcinogenesis

Although epidemiological evidence shows an association between arsenic in d rinking water and increased risk of skin, lung, and bladder cancers, arseni c compounds are not animal carcinogens. The lack of animal models has hinde red mechanistic studies of arsenic carcinogenesis. Previously, this laborat ory found that low concentrations of arsenite (the likely environmental car cinogen) which are not mutagenic can enhance the mutagenicity of other agen ts, including ultraviolet radiation (UVR). This enhancing effect appears to result from inhibition of DNA repair by arsenite. Recently we found that l ow concentrations of arsenite disrupted p53 function and upregulated cyclin D1. These results suggest that the failure to find an animal model for ars enic carcinogenesis is because arsenite is not a carcinogen per se, but rat her acts as an enhancing agent (cocarcinogen) with a genotoxic partner. We tested this hypothesis with solar UVR as carcinogenic stimulus in hairless Skh1 mice. Mice given 10 mg/l sodium arsenite in drinking water for 26 week s had a 2.4-fold increase in yield of tumors after 1.7 KJ/m(2) UVR three ti mes weekly compared with mice given UVR alone. No tumors appeared in mice g iven arsenite alone. The tumors were mostly squamous cell carcinomas, and t hose occurring in mice given UVR plus arsenite appeared earlier and were mu ch larger and more invasive than in mice given UVR alone. These results are consistent with the hypothesis that arsenic acts as a cocarcinogen with a second (genotoxic) agent by inhibiting DNA repair and/or enhancing positive growth signaling. (C) 2001 Academic Press.