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Transcriptomic dose-and-time-course indicators of early key events in a cytotoxicity-mediated mode of action for rodent urinary bladder tumorigenesis
Citation:
BHAT, V., S. Hester, C. Wood, M. Oliveria, J. Camargo, AND D. Eastmond. Transcriptomic dose-and-time-course indicators of early key events in a cytotoxicity-mediated mode of action for rodent urinary bladder tumorigenesis. Society of Toxicology, San Diego, CA, March 22 - 27, 2015.
Impact/Purpose:
To be presented at the annual Society of Toxicology Meeting 2015
Description:
TRANSCRIPTOMIC DOSE- AND TIME-COURSE INDICATORS OF EARLY KEY EVENTS IN A CYTOTOXICITY-MEDIATED MODE OF ACTION FOR RODENT URINARY BLADDER TUMORIGENESISDiuron is a substituted urea compound used globally as an herbicide. Urinary bladder tumors were induced in rats after chronic dietary exposures likely through a cytotoxicity-mediated mode of action (MOA). The present study estimates potency for activation of key functional pathways in this MOA identified from global gene expression profiling at 7 d and 20 wk and examines their concordance with apical key events over time, including urothelial cell cytotoxicity, proliferation, hyperplasia and ultimately tumors. The most sensitive urothelial pathways at 20 wk involved immune cell responses based on lower quartile (Q1) pathway transcriptional benchmark dose levels (BMDT) of 4-5 m/k-d, consistent with the apical benchmark dose (BMDA) of 4 m/k-d for urothelial cytotoxicity observed with scanning electron microscopy. Xenobiotic metabolism/detoxication and oxidative stress pathways were active at Q1 BMDT of 25-31 m/k-d, consistent with the BMDA for urothelial simple hyperplasia of 22 m/k-d at 20 wk and the suspected tumor threshold of 23-32 m/k-d at 2 y. A similar metabolic and oxidative stress response with comparable potency was seen at 7 d (Q1 BMDT of 18-25 m/k-d) without ultrastructural or histopathological evidence of urothelial alterations. Using a case study approach, this study demonstrates that dose responses corresponding to key MOA events and tumorigenic potency can be established from transcriptional effects following short-term exposure. Combined with previous or ongoing research with conazoles, phthalates and phenobarbital in mouse liver, our case studies encompass multiple species, target tissues, MOA, chemical classes and exposure durations of 2 d to 20 wk, thus demonstrating the utility of this approach as a chemical testing and prioritization strategy. This abstract does not reflect EPA policy.