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Concordance of Transcriptional and Apical Benchmark Dose Levels for Conazole-Induced Liver Effects in Mice
Citation:
Bhat, V., S. Hester, S. Nesnow, AND D. Eastmond. Concordance of Transcriptional and Apical Benchmark Dose Levels for Conazole-Induced Liver Effects in Mice. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 136(1):205-15, (2013).
Impact/Purpose:
The ability to anchor chemical class-based gene expression changes to phenotypic lesions and to describe these changes as a function of dose and time informs mode of action determinations and improves quantitative risk assessments.
Description:
ABSTRACT The ability to anchor chemical class-based gene expression changes to phenotypic lesions and to describe these changes as a function of dose and time informs mode of action determinations and improves quantitative risk assessments. Previous transcription-based microarray studies identified a 330-probe cluster differentially expressed and commonly responsive to three hepatotumorigenic conazoles (cyproconazole, epoxiconazole, propiconazole) at 30 days. Extended to two more conazoles (triadimefon and myclobutanil), the present assessment encompasses four tumorigenic and one non-tumorigenic conazole. Transcriptional benchmark dose levels (BMDLT) were estimated for a subset of the cluster with dose-responsive behavior and a ≥5-fold change in signal intensity at the highest dose. These genes primarily encompassed CAR/RXR activation, P450 metabolism, liver hypertrophy – glutathione depletion, LPS/IL-1 mediated inhibition of RXR, and NRF2-mediated oxidative stress pathways. Median BMDLT estimates from the subset were concordant (within a factor of 1.4) with apical benchmark doses (BMDLA) for increased liver weight at 30 days for the four tumorigenic conazoles. The 30-day median BMDLT estimates were within one-half order of magnitude of the chronic BMDLA for hepatocellular tumors. The non-tumorigenic conazole, myclobutanil, had more discordant 30-day BMDLT and BMDLA (2.4-fold). Potency differences seen in the dose-responsive transcription of certain Phase II metabolism, bile acid detoxification, and lipid oxidation genes mirrored each conazole’s tumorigenic potency. The 30-day BMDLT corresponded to tumorigenic potency on a mg/kg-day basis with cyproconazole > epoxiconazole > propiconazole > triadimefon > myclobutanil (non-tumorigenic). These results support the utility of measuring short-term gene expression changes to inform quantitative risk assessments from long-term exposures.