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New research sets the stage for development of an adverse outcome pathway for intestinal cancer

An article by ToxStrategies scientists and colleagues will appear soon in the journal Toxicologic Pathology. The authors report on a study of the transcriptomic profiles for three mouse small-intestine carcinogens: hexavalent chromium (Cr(VI)) and the fungicides captan and folpet. This work followed up on a previous study in which B6C3F1 mice exposed to carcinogenic concentrations of these agents for 28 days exhibited similar histopathological responses, including villus enterocyte cytotoxicity and regenerative crypt epithelial hyperplasia. Formalin-fixed, paraffin-embedded (FFPE) tissues were evaluated for transcriptomic responses to treatment using the TempO-Seq platform and the S1500+ gene set. Significant overlap was observed in the significantly differentially expressed genes between the three agents at the gene and pathway level, including changes related to cellular metabolism, stress, inflammatory/immune cell response, and cell proliferation. Up-regulation of hypoxia inducible factor 1 (HIF-1) and activator protein 1 (AP-1) signaling pathways was evident for the compounds, which have been shown to be related to intestinal injury and angiogenesis/carcinogenesis. Similarities in the molecular changes induced by these three intestinal mouse carcinogens, together with the previously reported common events at the cellular and tissue levels in these samples, can inform the understanding and future development of an adverse outcome pathway for intestinal cancer.

Chappell GA, Rager JE, Wolf J, Babic M, LeBlanc KJ, Ring CL, Harris MA, and Thompson CM. 2019 (in press). Comparison of gene expression responses in the small intestine of mice following exposure to 3 carcinogens using the S1500+ gene set informs a potential common adverse outcome pathway. Toxicologic Pathol.