| Arsenic Exposure Is Associated with Decreased DNA Repair in Vitro and in Individuals Exposed to Drinking Water Arsenic Angeline S. Andrew,1 Jefferey L. Burgess,2 Maria M. Meza,3 Eugene Demidenko,1 Mary G. Waugh,1 Joshua W. Hamilton,4 and Margaret R. Karagas1 1Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Dartmouth Medical School, Lebanon, New Hampshire, USA; 2Department of Environmental and Community Health, University of Arizona, Tucson, Arizona, USA; 3Department of Natural Resources, Technological Institute of Sonora (ITSON), Ciudad Obregon, Sonora, Mexico; 4Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA Abstract
The mechanism(s) by which arsenic exposure contributes to human cancer risk is unknown ; however, several indirect cocarcinogenesis mechanisms have been proposed. Many studies support the role of As in altering one or more DNA repair processes. In the present study we used individual-level exposure data and biologic samples to investigate the effects of As exposure on nucleotide excision repair in two study populations, focusing on the excision repair cross-complement 1 (ERCC1) component. We measured drinking water, urinary, or toenail As levels and obtained cryopreserved lymphocytes of a subset of individuals enrolled in epidemiologic studies in New Hampshire (USA) and Sonora (Mexico) . Additionally, in corroborative laboratory studies, we examined the effects of As on DNA repair in a cultured human cell model. Arsenic exposure was associated with decreased expression of ERCC1 in isolated lymphocytes at the mRNA and protein levels. In addition, lymphocytes from As-exposed individuals showed higher levels of DNA damage, as measured by a comet assay, both at baseline and after a 2-acetoxyacetylaminofluorene (2-AAAF) challenge. In support of the in vivo data, As exposure decreased ERCC1 mRNA expression and enhanced levels of DNA damage after a 2-AAAF challenge in cell culture. These data provide further evidence to support the ability of As to inhibit the DNA repair machinery, which is likely to enhance the genotoxicity and mutagenicity of other directly genotoxic compounds, as part of a cocarcinogenic mechanism of action. Key words: arsenic, arsenite, DNA repair, ERCC1, molecular epidemiology, nucleotide excision repair. Environ Health Perspect 114:1193–1198 (2006) . doi:10.1289/ehp.9008 available via http://dx.doi.org/ [Online 10 May 2006]
Address correspondence to A.S. Andrew, Dartmouth Medical School, Section of Biostatistics and Epidemiology, 7927 Rubin 860, One Medical Center Dr., Lebanon, NH 03756 USA. Telephone: (603) 653-9019. Fax: (603) 653-9093. E-mail: Angeline.Andrew@dartmouth.edu Funding was provided by the National Institutes of Health [NIH ; CA099500, CA82354, and CA57494 from the National Cancer Institute and ES00002, ES05947, RR018787, ES06694, and ES07373 from the National Institute of Environmental Health Sciences (NIEHS) ], the Dartmouth and Arizona Superfund Programs, and the American Society of Preventive Oncology (ASPO) . The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH, or ASPO. The authors declare they have no competing financial interests. Received 12 January 2006 ; accepted 10 May 2006.
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