Kim S, Kopec A, Forgacs AL, Thompson CM, Zacharewski T. 2012. Genome-wide gene expression analysis of Cr(VI) effects in Fisher rat small intestinal epithelium. Presented at the Society of Toxicology’s 51st Annual Meeting, March 11-15, San Francisco, CA.
Chronic exposure to hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) leads to intestinal tumors in mice, and oral cancers and mild hypoferremia in rats. In this study, the dose-dependent gene expression effects of SDD (0.3-520 mg/L) were evaluated in female Fischer rat duodenal and jejunal epithelia following 7 and 90 days of exposure in drinking water. Agilent 4x44K wholegenome microarrays identified 3269 and 1815 duodenal, and 4557 and 1534 jejunal differentially expressed genes (|fold change|>1.5, P1(t)>0.999) at days 8 and 91, respectively. Comparisons at day 8 showed significant overlap (2312 genes) between duodenal and jejunal gene expression, with the former exhibiting greater efficacy (i.e. maximum fold change). The overlap was ~50% lower at day 91 with comparable fold inductions in both tissues. Automated analysis identified 744 and 310 duodenal and 1021 and 167 jejunal genes exhibiting sigmoidal dose-response profiles at 8 and 91 days, respectively. At 8 days, the interquartile EC50 range overlapped between duodenum and jejunum, but the median EC50 was ~10 times lower in duodenum (5 mg/L) compared to jejunum (52 mg/L). At 91 days, the median EC50 values were comparable between duodenum (49 mg/L SDD) and jejunum (59 mg/L SDD). Functional annotation identified differential expression associated with oxidative stress, cell cycle, cell death and immune response, consistent with changes in GSH/GSSG levels, crypt hyperplasia, apoptosis and inflammation. QRT-PCR confirmed induction of oxidative stress genes, including Gpx2 and Gclc. Genes involved in dietary iron absorption/transport were also repressed, suggesting SDD may interfere with iron homeostasis. These results indicate that, like the mouse, the rat intestinal epithelium is responsive to Cr(VI). Comparisons of gene expression changes in rats and mice should inform the mode of action underlying the different tumor outcomes in the small intestine. Funded by the ACC Cr(VI) Panel.