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Application of Toxicogenomics to Develop a Mode of Action for a Carcinogenic Conazole Fungicide
Citation:
NESNOW, S., J. W. ALLEN, C. F. BLACKMAN, P. CHEN, Y. GE, S. D. HESTER, L. C. KING, P. A. ORTIZ, J. A. ROSS, S. Y. THAI, W. O. WARD, W. M. WINNIK, AND D. C. WOLF. Application of Toxicogenomics to Develop a Mode of Action for a Carcinogenic Conazole Fungicide. Presented at NAS Symposium on Toxicity Pathway-Based Risk Assessment: Preparing for Paradigm Change, Washington, DC, May 11 - 13, 2009.
Impact/Purpose:
Abstract/Poster to be presented at the NAS Symposium on Toxicity Pathway-Based Risk Assessment: Preparing for Paradigm Change
Description:
Conazoles are a common class of fungicides used to control fungal growth in the environment and in humans. Some of these agents have adverse toxicological outcomes in mammals as carcinogens, reproductive toxins, and hepatotoxins. We coupled the results from genomic analyses with traditional laboratory investigations (toxicology, molecular biology and biochemistry) to propose a mode of action (MOA) for the carcinogenic activity of propiconazole in mouse liver. A key element of the approach was to use activity-inactivity pairs of conazoles. This allowed the sequestration of the genomic results toward the toxicologic endpoints, and provided a rapid method to identify genes, pathways, and networks that could be responsible for the observed toxic effects. Conazoles are designed to inhibit CYP51, a central step in the biosynthesis of ergosterol in fungal systems, and ergosterol, cholesterol, Vitamin D and the sex steroids in mammalian systems. Conazoles are pleiotropic; they can both induce and inhibit mammalian CYPs and these characteristics, in part, help to explain their varied toxic activities. We performed both dose response and time course studies in mice to develop and characterize key events in the MOA that can describe the propiconazole-induced carcinogenic process. These studies provided data on the following series of key events in the carcinogenic MOA of propiconazole: nuclear receptor activation, Cyp induction, decreases in hepatic retinoic acid levels, increased oxidative stress, decreases in serum cholesterol levels, increases in mevalonic acid levels, increased cell proliferation, decreased apoptosis, and the induction of in vivo mutagenicity. These key events have been synthesized into a MOA that describes the carcinogenic process induced by propiconazole in mouse liver. This abstract does not represent EPA Policy