Transcriptomic signatures indicative of a non-genotoxic adverse outcome pathway for small intestine cancer in the duodenum of mice exposed to hexavalent chromium, captan, or folpet

We evaluated duodenal tissues of B6C3F1 mice exposed to either Cr(VI) (180ppm in drinking water), captan (≤12000ppm in diet), or folpet (≤16000ppm in diet) for 28 days. TempO-Seq technology was used to measure the sentinel geneset, S1500+, representing ~3000 toxicology-relevant genes. Global exposure-induced transcriptional responses were similar between agents (all Pearson correlation coefficients ≥0.61). Focusing on responses at doses of captan and folpet that correlate most closely with effects of Cr(VI), a gene-level comparison identified that 126/546 (23%) differentially expressed genes were altered in the same direction across all three agents. Pathway-level comparisons identified 25 up-regulated pathways commonly modulated between Cr(VI), captan, and folpet. Commonly altered genes and pathways were related to cellular metabolism, stress, immune response, and cell proliferation. No up-regulated pathways relevant to genotoxicity were associated with responses to any agent. Examination of ~3000 genes by targeted sequencing in duodenal tissue from mice from 6 treatment groups.