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FOLATE DEFICIENCY ENHANCES ARSENIC EFFECTS ON EXPRESSION OF GENES INVOLVED IN EPIDERMAL DIFFERENTIATION
Citation:
NELSON, G. M., G. AHLBORN, D. A. DELKER, K. T. KITCHIN, M. J. KOHAN, B. ROOP, W. O. WARD, J. W. ALLEN, AND T. O'BRIEN. FOLATE DEFICIENCY ENHANCES ARSENIC EFFECTS ON EXPRESSION OF GENES INVOLVED IN EPIDERMAL DIFFERENTIATION. Presented at Society of Toxicology Annual Meeting 2007, Charlotte, NC, March 25 - 29, 2007.
Description:
Chronic arsenic exposure in humans is associated with cancers of the skin, lung, and bladder. There is evidence that folate deficiency may increase susceptibility to arsenic¿s effects, including arsenic-induced skin lesions. K6/ODC mice develop skin tumors when exposed to 10 ppm sodium arsenite for 5 months. In the current study, K6/ODC mice maintained on either a folate-deficient or a folate-sufficient diet were exposed to 0, 1, or 10 ppm sodium arsenite in the drinking water for 30 days. Total RNA was isolated from skin samples and gene expression analyzed using Affymetrix Mouse 430 2.0 GeneChips. Data from 24 samples, with four mice in each of the six treatment groups, were RMA normalized and analyzed by two-way ANOVA using GeneSpringTM . . Top gene ontology (GO) categories for genes responding significantly to both arsenic treatment and folate deficiency include DNA metabolism, DNA replication, sulfur metabolism and epithelial cell differentiation. For these genes, folate deficiency magnifies the response to arsenic treatment. In particular, expression of markers of epidermal differentiation such as loricrin, small proline rich proteins, and involucrin was significantly reduced by arsenic in the folate-sufficient animals, and reduced further or at a lower arsenic dose in the folate-deficient animals. In addition, several genes involved in epidermal cell growth were up-regulated by arsenic treatment, but folate status did not consistently affect their expression. The suppressive effect of arsenic on epidermal differentiation marker expression in cultured human keratinocytes has been reported in the literature. This may point to a mechanism of neoplasia in which the cells are blocked from achieving the normal state of differentiation and remain capable of proliferation. Our in vivo results suggest that dietary folate deficiency may exacerbate this effect.