Gene Expression Profiling in Testis and Liver of Mice to Identify Modes of Action of Conazole Toxicities

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Title: Gene Expression Profiling in Testis and Liver of Mice to Identify Modes of Action of Conazole Toxicities
Author: Goetz, Amber Kristina
Advisors: Dr. Charlotte Farin, Committee Member
Dr. Robert C Smart, Committee Co-Chair
Dr. David J Dix, Committee Co-Chair
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 daily 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 liver and testis affected similar biological pathways, suggesting the potential for common modes of action.
Date: 2004-02-16
Degree: MA
Discipline: Toxicology

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