Inorganic arsenic is a known human carcinogen, yet its mechanism of action remains poorly understood. Epidemiological data suggest that arsenic exposure interacts with UV radiation exposure to increase the risk of skin cancer. Studies have suggested that arsenic is able to impair DNA repair enzymes and alter the repair of UV-induced DNA damage. Here we have tested the hypothesis that arsenite [As(III)] and UV interact synergistically to enhance mutagenesis. TK6 human lymphoblastoid cells that are functionally heterozygous at the thymidine kinase (TK) locus were pre-exposed to As(III) alone and in combination with UV. Our data suggest that As(III) is mutagenic only at high doses at the TK locus. As(III) enhanced UV mutagenesis in a more than additive fashion. To investigate the mechanism underlying this synergy we assessed the removal of UV-induced dimers in TK6 cells using the T4 endonuclease-incorporated Comet assay. Pre-treatment with As(III) specifically inhibited the repair of UV-induced pyrimidine dimer-related DNA damage. Taken together, these data suggest that pre-treatment of human cells with arsenic impairs the nucleotide excision repair pathway and leads to enhanced UV mutagenesis.
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We would like to thank Drs Joe Paulauskis, Russ Hauser, Margaret Karagas and Louise Ryan for thoughtful discussions. We are also grateful to Amy Imrich for help with the flow cytometry, Ana Trisini and Ramace Dadd (Hauser Laboratory) for their expertise in the Comet assay and Brisa Sanchez for statistical advice. This publication was made possible by grant no. 5 P43 ES05947 from the NIEHS. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the NIEHS. The work was also supported by grants T32 CA09078, CA82354 and CA57494.