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Denis Ganyc,¹ Sarah Talbot,¹ Fanta Konate,¹ Sarah Jackson,¹ Brian Schanen,¹ William Cullen,² and William T. Self¹

¹Department of Molecular Biology and Microbiology, Burnett College of Biomedical Science, University of Central Florida, Orlando, Florida, USA; ²Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada

Abstract
Background: Exposure to arsenic has been associated with development of skin, lung, bladder, liver, and kidney cancer. Recent evidence suggests that an increase in oxidative stress in cells treated with arsenicals represents the molecular mechanism behind arsenic-induced carcinogenesis. Selenium, in the form of selenocysteine, is necessary for the activity of several enzymes with a role in defense against reactive oxygen species. A mutual sparing effect between arsenic and selenium has been shown in animal studies when both metalloids are present in high concentrations.

Objectives: To determine whether changes in selenoprotein synthesis may be an underlying mechanism behind arsenic-induced carcinogenesis, we analyzed the new synthesis of selenoproteins within cells after exposure to inorganic or methylated arsenicals using a human keratinocyte cell model.

Results: Addition of arsenite to culture medium blocked new synthesis of selenoproteins when selenium was present in the form of selenite, and appeared to stimulate the use of serum-derived selenium. Monomethylarsonous acid (MMA^III) treatment of cells, in contrast, did not block all new synthesis of selenoproteins but did result in an increase in cytosolic thioredoxin reductase (TrxR1) at both the mRNA and protein levels. MMA^III also reduced the new synthesis of cellular glutatione peroxidase (cGpx) and other smaller selenoproteins. Dimethylarsinous acid (DMA^III) stimulated selenoprotein synthesis by an as yet unknown mechanism.

Conclusions: These results suggest that arsenite and MMA^III are key metabolites that trigger higher levels of TrxR1, and both lead to a reduction in the expression of cGpx. Together these effects certainly could lead to carcinogenesis given the knowledge that many cancers have higher levels of TrxR, and reduced Gpx levels will reduce the cell's ability to defend against reactive oxygen species. Based on these results, the impact of the trivalent arsenicals arsenite and MMA^III on selenoprotein synthesis may indeed represent a potential molecular mechanism for the higher rates of cancer observed in populations exposed to high levels of arsenic.

Key words: arsenite, dimethylarsinous acid, glutathione peroxidase, monomethylarsonous acid, selenite, thioredoxin reductase. Environ Health Perspect 115:346–353 (2007) . doi:10.1289/ehp.9440 available via http://dx.doi.org/ [Online 19 December 2006]

Address correspondence to W. Self, Department of Molecular Biology and Microbiology, Burnett College of Biomedical Science, 4000 Central Florida Blvd., Bldg. 20, Rm. 124, University of Central Florida, Orlando, FL 32816-2364 USA. Telephone: (407) 823-4262. Fax: (407) 823-0956. E-mail: wself@mail.ucf.edu

We thank N. Fusenig from the Division of Differentiation and Carcinogenesis, German Cancer Research Center for supplying the keratinocyte cell line HaCat, and T.C. Stadtman for providing the antibodies to TrxR1. We also thank A. Cole for the use of his luminometer.

This research was supported by grants to W.T.S. from the National Institute of Environmental Health Sciences (ES01434) and the Florida Department of Health (05-NIR-10) .

The authors declare they have no competing financial interests.

Received 21 June 2006 ; accepted 19 December 2006.