Comparative toxicogenomic analysis of oral Cr(VI) exposure effects in rat and mouse small intestinal epithelia

• Published in: Toxicology and applied pharmacology 2012-07, Vol.262 (2), p.124-138
• Main Authors: Kopec, Anna K., Thompson, Chad M., Kim, Suntae, Forgacs, Agnes L., Zacharewski, Timothy R.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Biological and medical sciences; Carcinogens, Environmental - toxicity; CELL CYCLE; Cell death; Chemical and industrial products toxicology. Toxic occupational diseases; CHROMIUM; Chromium - toxicity; Cr(VI); Data processing; DICHROMATES; DNA microarrays; Dose-Response Relationship, Drug; DOSES; DRINKING WATER; Duodenum; FASTENING; Female; Gene expression; GENES; Immune response; Intestinal Neoplasms - chemically induced; Intestinal Neoplasms - genetics; Intestine; Intestine, Small - drug effects; Intestine, Small - metabolism; Intestine, Small - pathology; Medical sciences; Metals and various inorganic compounds; MICE; Mice, Inbred C57BL; Microarray; NEOPLASMS; Oligonucleotide Array Sequence Analysis; Ortholog; OXIDATION; Oxidative stress; Phenotypic anchoring; RATS; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; RNA - chemistry; RNA - genetics; SMALL INTESTINE; sodium dichromate; Species Specificity; Toxicogenomics; Toxicology; Tumors
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.04.026

Continuous exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water results in intestinal tumors in mice but not rats. Concentration-dependent gene expression effects were evaluated in female F344 rat duodenal and jejunal epithelia following 7 and 90days of exposure to 0.3–520mg/L (as sodium dichromate dihydrate, SDD) in drinking water. Whole-genome microarrays identified 3269 and 1815 duodenal, and 4557 and 1534 jejunal differentially expressed genes at 8 and 91days, respectively, with significant overlaps between the intestinal segments. Functional annotation identified gene expression changes associated with oxidative stress, cell cycle, cell death, and immune response that were consistent with reported changes in redox status and histopathology. Comparative analysis with B6C3F1 mouse data from a similarly designed study identified 2790 differentially expressed rat orthologs in the duodenum compared to 5013 mouse orthologs at day 8, and only 1504 rat and 3484 mouse orthologs at day 91. Automated dose–response modeling resulted in similar median EC50s in the rodent duodenal and jejunal mucosae. Comparative examination of differentially expressed genes also identified divergently regulated orthologs. Comparable numbers of differentially expressed genes were observed at equivalent Cr concentrations (μg Cr/g duodenum). However, mice accumulated higher Cr levels than rats at ≥170mg/L SDD, resulting in a ~2-fold increase in the number of differentially expressed genes. These qualitative and quantitative differences in differential gene expression, which correlate with differences in tissue dose, likely contribute to the disparate intestinal tumor outcomes. ► Cr(VI) elicits dose-dependent changes in gene expression in rat intestine. ► Cr(VI) elicits less differential gene expression in rats compared to mice. ► Cr(VI) gene expression can be phenotypically anchored to intestinal changes. ► Species-specific and divergent changes are consistent with species-specific tumors.