Toxicogenomic Study of Triazole Antifungal Modes of Action

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Title: Toxicogenomic Study of Triazole Antifungal Modes of Action
Author: Goetz, Amber Kristina
Advisors: 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
Abstract: 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.
Date: 2007-09-11
Degree: PhD
Discipline: Toxicology

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