Mutagenesis vol. 19 no. 2 pp. 143-148,
March 2004
© 2004 UK Environmental Mutagen Society/Oxford University Press
Low dose exposure to sodium arsenite synergistically interacts with UV radiation to induce mutations and alter DNA repair in human cells
1Department of Cancer Cell Biology and 2Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115-6021, USA and 3Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA
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.
4To whom reprint requests should be addressed. Tel: +1 617 432 3313; Fax: +1 617 432 0107; Email: kelsey{at}hsph.harvard.edu
Received on August 20, 2003; revised on November, 17, 2003; accepted on November 25, 2003
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