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

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.
Date18 November 2003
CreatorsGoetz, Amber Kristina
ContributorsDr. Charlotte Farin, Dr. Robert C Smart, Dr. David J Dix
Source SetsNorth Carolina State University
Detected LanguageEnglish
Rightsunrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report.

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