Browsing by Author "Goetz, Amber Kristina"

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    Gene Expression Profiling in Testis and Liver of Mice to Identify Modes of Action of Conazole Toxicities
    (2004-02-16) Goetz, Amber Kristina; Dr. Charlotte Farin, Committee Member; Dr. Robert C Smart, Committee Co-Chair; Dr. David J Dix, Committee Co-Chair
    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.
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    Toxicogenomic Study of Triazole Antifungal Modes of Action
    (2007-09-11) Goetz, Amber Kristina; Dr. Russ Wolfinger, Committee Member; Dr. Andrew Wallace, Committee Member; Dr. David Dix, Committee Co-Chair; Dr. Charlotte Farin, Committee Member; Dr. Ernest Hodgson, Committee Co-Chair
    Common modes and mechanisms of hepatic and reproductive toxicity were characterized for a set of triazole antifungals. Wistar Han rats were fed myclobutanil, propiconazole, or triadimefon from gestation day 6 to postnatal day (PND) 120. Anogenital distance, body and organ weights, serum hormone levels, age at preputial separation, sperm morphology and motility, fertility and fecundity assays were selected to evaluate effects on development and adult reproductive function. All three triazoles increased anogenital distance, increased relative liver weights, induced hepatomegaly, increased absolute testis weights and serum testosterone levels. Myclobutanil and triadimefon impaired insemination and fertility, myclobutanil decreased pituitary weights, and triadimefon delayed puberty and decreased total serum thyroxine levels. The reproductive effects are consistent with disruption of testosterone homeostasis as a key event for triazole reproductive toxicity. To investigate common mechanisms of triazole toxicity, a toxicogenomic study was performed using liver and testis samples from PND92. Pathway and gene-level analysis of the liver highlighted biological processes affected by all three triazoles, including phase I-III; fatty acid, steroid, and xenobiotic metabolism; and lipid homeostasis. Triadimefon had a distinctive impact on sterol biosynthesis related genes in the liver. No common pathways were affected in the testis. To explore common mechanisms of action between in vivo and in vitro model systems, a series of comparative toxicogenomic studies were conducted on rat liver at multiple time points, rat and human primary hepatocytes, H295R cells, and liver and testis from the initial study. Comparison between liver and rat hepatocytes showed consistent effect on fatty acid catabolism, sterol metabolism, and phase III transporters. Conserved effects between rat and human primary hepatocytes concluded triazole- and species-specific effects. The modulated genes affect a network of pathways regulating lipid and testosterone homeostasis through the constitutive androstane and pregnane X receptors. The gene expression results from this study suggest triazoles increase fatty acid catabolism, reduce bile acid biosynthesis, increase cholesterol biosynthesis, and induce steroid metabolism in the liver. These changes in the liver likely contribute to the observed disruption in testosterone homeostasis.