EPA Science Inventory

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, 136(1):205-15, (2013).

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.

Purpose/Objective:

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.

URLs/Downloads:

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Start Date: 11/01/2013
Completion Date: 11/01/2013
Record Last Revised: 07/28/2014
Record Created: 12/19/2013
Record Released: 12/19/2013
OMB Category: Other
Record ID: 265056

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

INTEGRATED SYSTEMS TOXICOLOGY DIVISION

SYSTEMS BIOLOGY BRANCH