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The hepatocarcinogenic conazoles: cyproconazole, epoxiconazole, and propiconazole induce a common set of toxicological and transcriptional responses
Citation:
HESTER, S. D., T. MOORE, W. PADGETT, L. A. MURPHY, C. E. Wood, AND S. NESNOW. The hepatocarcinogenic conazoles: cyproconazole, epoxiconazole, and propiconazole induce a common set of toxicological and transcriptional responses. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 127(1):54-65, (2012).
Impact/Purpose:
The goals of this study were to apply toxicological and transcriptomic approaches to develop a toxicity profile for hepatocarcinogenic conazoles using cyproconazole, epoxiconazole and propiconazole.
Description:
Conazoles are fungicides used as agricultural pesticides and pharmaceutical products. The mechanism of conazole-induced liver carcinogenesis in mice has been the subject of intensive investigations. The goals of this study were 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-l 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. These conazoles induced hepatomegaly and hepatocellular hypertrophy, decreased serum cholesterol and hepatic levels of all-trans retinoic acid, and increased hepatic cell proliferation. Microarray-based transcriptional analysis revealed 330 probesets significantly altered common to these conazoles, many which showed strong dose responses for cytochrome P450 activity, glutathione S-transferase and oxidative stress. More detailed analyses identified a subset of 80 altered genes common to the three conazoles that were associated with cancer. Pathways associated with these genes included xenobiotic metabolism, oxidative stress, cell signaling, and cell proliferation. A common TGFa-centric pathway was identified within the 80 gene set which, in combination with the toxicological and other transcriptomic findings, provides a more refined toxicity profile for these tumorigenic conazoles.
