Harris MA, Thompson CM, Wolf JC, Fedorov Y, Hixon JG, Proctor DM, Suh M, Haws LC. 2012. Assessment of genotoxic potential of Cr(VI) in the intestine via in vivo intestinal micronucleus assay and in vitro high content analysis in differentiated and undifferentiated caco-2. Presented at the Society of Toxicology’s 51st Annual Meeting, March 11-15, San Francisco, CA.
Chronic exposure to high concentrations of hexavalent chromium [Cr(VI)], in the form of sodium dichromate dihydrate (SDD), in drinking water has been shown to induce intestinal tumors in mice. As a part of a larger study investigating the mode action (MOA) underlying these tumors, whole-genome microarray data were collected from the mouse duodenum after 7 days of exposure to 0.3-520 mg/L SDD in drinking water. Analysis of Cr(VI)-induced differential intestinal gene expression was conducted and compared to a set of genes previously analyzed for their ability to discriminate genotoxic and nongenotoxic carcinogens in rats following short term (≤14 days) exposure to 8 hepatocarcinogens. To allow for direct comparison between the two studies, significant ortholog gene changes from the rat studies were mapped to mouse data from the Cr(VI) study using HomoloGeneIDs. Genes from 7 categories (e.g. oxidative stress/DNA response, oxidative stress/protein damage response) were highlighted for potentially distinguishing between genotoxic and nongenotoxic carcinogens. There were 139 significantly altered rat genes among these 7 categories, of which 116 orthologs could be mapped to mouse gene expression in the 520 mg/L SDD treatment group. Principal components analysis of these orthologs reduced the dataset to 3 principal components, accounting for ~82% of the overall variance. Cluster analysis with the principal components indicated that the 4 genotoxic carcinogens clustered together, and apart from the 4 nongenotoxic carcinogens. When gene expression data for Cr(VI) was analyzed, it clustered closely with the nongenotoxic carcinogens. These findings, together with other results from our MOA studies, lend support to the hypothesis that Cr(VI) acts through a nonmutagenic MOA in the mouse small intestine.