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Development of a toxicity profile for the hepatocarcinogenic conazoles: cyproconazole, epoxiconazole, and propiconazole
Citation:
NESNOW, S., T. MOORE, W. PADGETT, L. A. MURPHY, C. E. WOOD, AND S. D. HESTER. Development of a toxicity profile for the hepatocarcinogenic conazoles: cyproconazole, epoxiconazole, and propiconazole. Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2011.
Impact/Purpose:
The motivation for this study was to apply toxicological and transcriptomic approaches to develop a toxicity profile for hepatocarcinogenic conazoles using cyproconazole, epoxiconazole and propiconazole.
Description:
Conazoles are fungicides used in farming as pesticides and in medicine as pharmaceutical agents. The mechanism of conazole-liver carcinogenesis in mice has been the subject of intensive investigations. The motivation for this study was to apply toxicological and transcriptomic approaches to develop a toxicity profile for hepatocarcinogenic conazoles using cyproconazole, epoxiconazole and propiconazole. In the current study, male CD-1 mice were fed dietary levels of cyproconazole (0, 50, 100, or 200 ppm), epoxiconazole (0, 50, 200, or 500 ppm) or propiconazole (0, 500, 1250 or 2500 ppm) for 30 d. Each conazole induced hepatomegaly and hepatocyte hypertrophy, decreased serum cholesterol and hepatic levels of all-trans retinoic acid, and increased hepatic cell proliferation. Microarray-based transcriptional analysis revealed 330 differentially expressed probesets common among these conazoles, including strong dose-dependent responses for CYPs, glutathione S-transferases, and markers of oxidative stress. Further analyses identified an 80 gene subset common to the three conazoles that were functionally related to cancer. Within these genes were pathways associated with xenobiotic metabolism, oxidative stress, cell signaling, and cell proliferation. A common TGFα-centric gene signaling pathway was identified that explains the positive effects on proliferation produced by these tumorigenic conazoles. (This abstract does not reflect EPA policy and mention of trade names is not an endorsement for any product).