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GENE EXPRESSION PROFILING IN TESTIS AND LIVER OF MICE TO IDENTIFY MODES OF ACTION OF CONAZOLE TOXICITIES
Citation:
Goetz, A K., W Bao, J E. Schmid, C R. Wood, H. Hongzu Ren, D S. Best, R. N. Murrell, J. John C. Rockett, M G. Narotsky, D C. Wolf, D B. Tully, AND D J. Dix. GENE EXPRESSION PROFILING IN TESTIS AND LIVER OF MICE TO IDENTIFY MODES OF ACTION OF CONAZOLE TOXICITIES. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
Gene Expression Profiling in Testis and Liver of Mice to Identify MODES OF ACTION OF Conazole TOXICITies
Amber K. Goetz1, Wenjun Bao2, Judith E. Schmid2, Carmen Wood2, Hongzu Ren2, Deborah S. Best2, Rachel N. Murrell1, John C. Rockett2, Michael G. Narotsky2, Douglas C. Wolf2, Douglas B. Tully2, David J. Dix2
1 Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC
2 National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, RTP, NC
ABSTRACT
Conazoles are a class of azole fungicides used in both pharmaceutical and agricultural applications. This study focused on 4 conazoles that exhibit a range of carcinogenic and reproductive effects, in order to identify common and unique modes of action. Conazoles target cytochrome P450s (CYPs), and the inhibition and induction of various CYP activities may be part of the toxic modes of action in liver and testis. We used gene expression profiling to characterize a broader range of conazole effects and to identify additional modes of action. Adult male CD-1 mice were dosed by gavage for 14 days with fluconazole, propiconazole, myclobutanil or triadimefon (three doses each). Relative liver weight increased following fluconazole and propiconazole exposure, and histological analysis revealed centrilobular hepatocyte hypertrophy in response to all 4 conazoles. No weight or histological changes were observed in testis, and serum testosterone and luteinizing hormone were also unchanged. Microarrays queried expression of 16,475 genes, and identified 2,081 and 1,424 differentially expressed genes in liver and testis, respectively, following conazole exposure. Of these genes, 118 in the liver and 94 in the testis were common to two or more conazoles. The majority of differentially expressed genes related to stress response, oxidative stress, xenobiotic metabolizing enzymes, steroidogenesis or carcinogenesis. Expression profiles between conazoles and between tissues affected similar biological pathways, suggesting the potential for common modes of action. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy. Funded in part by EPA Cooperative Training Agreement CT826512010 with North Carolina State University.