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DOES RESPONSE EVALUATION OF GENE EXPRESSION PROFILES IN THE SKIN OF K6/ODC MICE EXPOSED TO SODIUM ARSENITE
Citation:
AHLBORN, G., G. M. NELSON, W. O. WARD, G. W. KNAPP, J. W. ALLEN, M. OUYANG, Y. CHEN, T. O'BRIEN, K. T. KITCHIN, AND D. A. DELKER. DOES RESPONSE EVALUATION OF GENE EXPRESSION PROFILES IN THE SKIN OF K6/ODC MICE EXPOSED TO SODIUM ARSENITE. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 227(3):400-416, (2008).
Impact/Purpose:
Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, gene expression profiles were characterized from analysis of K6/ODC mice.
Description:
Abstract - Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, gene expression profiles were characterized from analysis of K6/ODC mice administered 0, 0.05, 0.25, 1.0 and 10 ppm sodium arsenite in their drinking water for 4 weeks. Following exposure, total RNA was isolated from mouse skin and processed to biotin labeled cRNA for microarray analyses. Skin gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 GeneChips® and pathway analysis was conducted with DAVID (NIH), Ingenuity® Systems and MetaCore’s GeneGo. Only the highest dose (10 ppm) resulted in significantly altered KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, including MAPK, regulation of actin cytoskeleton, Wnt, Jak-Stat, Tight junction, Toll-like, phosphatidylinositol, and insulin signaling pathways. Approximately 20 genes exhibited a dose response, including several genes known to be associated with carcinogenesis or tumor progression including Cyclin D1, CLIC4, Ephrin A1, STAT3 and DNA methyltransferase 3a. Although transcription changes in all identified genes have not previously been linked to arsenic carcinogenesis, their association with carcinogenesis in other systems suggests that these genes may play a role in the early stages of arsenic-induced skin carcinogenesis and can be considered potential biomarkers.
What is the study? Three companion studies were performed in K6/ODC transgenic mice to evaluate dose-response relationships associated with skin gene expression changes following drinking water exposures to inorganic arsenic or monomethylarsonous acid, an organic form of arsenic. The effects of dietary folate deficiency on patterns of arsenic-induced changes in gene expression were also evaluated.
Why was it done? K6/ODC transgenic mice are known to reveal a dose-dependent tumorigenic response in skin following treatment with arsenic. We have performed gene expression dose-response studies in normal appearing skin and in squamous papillomas induced by arsenical treatment in order to characterize the molecular events involved in arsenical-induced skin carcinogenesis. We have used doses that are known to induce cancer and that are commonly found in the environment to better estimate potential human hazards to arsenic found in drinking water. This unique rodent model provides an opportunity to identify patterns of altered gene expression which may have mode of action implications, as well as susceptibility factors which may modulate gene response. The impact of folate deficiency on arsenic changes in gene expression is of mechanistic interest in relation to increasing epidemiological studies that have identified low levels of this B vitamin as a nutritional susceptibility factor for arsenic-induced skin lesions/cancers. This research is aimed at reducing uncertainties in assessment of arsenic risk for human health.
What is the impact to the field and the agency? Our results indicate that arsenic disrupts the normal balance of keratinocyte cell proliferation and differentiation; furthermore, dietary folate deficiency exacerbates these effects. We have also identified novel cellular signaling pathways that provide added information regarding molecular mechanisms involved in arsenical induced dedifferentiation and cell proliferation as well as confirm previous molecular targets of arsenic including AP-1 transcription factor activation. Based on the activation of these pathways we have characterized the gene expression dose response of select effectors of these pathways. These findings provide the first delineation of genes and gene categories that are altered in expression for skin of mice known to develop arsenic exposure-related skin tumors. They also provide support for the view that folate deficiency is a nutritional susceptibility factor for arsenic-induced skin tumorigenesis.
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DOES RESPONSE EVALUATION OF GENE EXPRESSION PROFILES IN THE SKIN OF K6/ODC MICE EXPOSED TO SODIUM ARSENITE