Chappell GA, Rager JE, Wolf JC, Babic M, LeBlanc KJ, Ring CL, Harris MA, Thompson C. Similarities in the transcriptomic signatures in the duodenum of mice exposed to hexavalent chromium, captan, or folpet inform the mechanisms of chemical-induced mouse small intestine cancer. Presentation at Society of Toxicology Annual Meeting, Baltimore, MD, March 2019.
Shared key events observed in intestinal cancers in mice exposed orally to hexavalent chromium [Cr(VI)], captan, or folpet suggest similar non-genotoxic modes of action, based on comparable histopathological findings in the duodenum (e.g. villus enterocyte cytotoxicity and crypt epithelial hyperplasia). Based on these similarities, we hypothesized that transcriptomic responses in the duodenum are also similar across these three agents. Such similarities at the molecular level would support a common adverse outcome pathway (AOP) for chemically-induced mouse intestinal carcinogenesis. We tested this hypothesis by evaluating transcriptomic responses in the duodenal tissues of B6C3F1 mice exposed to either Cr(VI) (180ppm, drinking water), captan (=<12000ppm, diet), or folpet (=<16000ppm, diet) for 28 days, using TempOSeq to measure expression of the S1500+ genes. Transcriptomic responses were compared by three approaches: first, global gene expression profiles were similar between agents, with overall Pearson correlation coefficients >0.6. Second, gene-specific overlap comparisons revealed that 126/546 (23%) differentially expressed genes were altered in the same direction across all three agents. Third, gene set enrichment analysis was conducted using a broad range of curated gene sets, with 39 (23%) gene sets commonly modulated between Cr(VI) and captan or folpet. A total of 25 upregulated gene sets were modulated by all three compounds, which were related to cellular metabolism, stress, inflammatory/immune cell response, and cell proliferation, including upregulation in HIF1- and AP1-signaling pathways (which are related to intestinal injury and angiogenesis/carcinogenesis). Transcriptomic profiles also differed between crypt and villus cells, indicating that alterations at the gene expression level are cell type-specific. There was a lack of enrichment of DNA damage response-related gene sets. The similarities in Cr(VI)-, captan-, and folpet-induced effects at the molecular level support an AOP for mouse intestinal cancer that involves cytotoxic mechanisms.