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Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals
Citation:
GOETZ, A. AND D. J. DIX. Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 110(2):449-62, (2009).
Impact/Purpose:
The gene expression profiles in this study have provided strong support for a mode of action for reproductive and hepatic toxicity, mediated through the CAR and PXR signaling pathways and common to the triazole antifungals.
Description:
The mode of action for the reproductive toxicity of triazole antifungals have been previously characterized by an observed increased in serum testosterone, hepatotoxicity, and reduced insemination and fertility indices. In order to refine our mechanistic understanding of these modes of action, gene expression profiling was conducted on liver and testis from Wistar Han IGS rats fed myclobutanil (500, 2000 ppm), propiconazole (500, 2500 ppm), or triadimefon (500,1800 ppm) from gestation day six (GD6) to postnatal day 92 (PND92). Gene expression profiles indicated that all three triazoles significantly perturbed the fatty acid, steroid, and xenobiotic metabolism pathways in the rat liver. In addition, triadimefon modulated expression of genes in the liver from the sterol biosynthesis pathway. There were no common pathways modulated by all three triazoles in the testis. The pathways identified in the liver included numerous genes involved in phase I-III metabolism (Aldh1a1, Cyp1a1, Cyp2b2, Cyp3a1, Cyp3a2, Slco1a4, Udpgtr2), fatty acid metabolism (Cyp4a10, Pcx, Ppap2b), and steroid metabolism (Ugt1a1, Ugt2a1) for which expression was altered by the triazoles. These differentially expressed genes are part of a network of lipid, sterol and steroid homeostatic pathways regulated by the constitutive androstane (CAR), pregnane X (PXR), peroxisome proliferator-activated alpha (PPARα), and other nuclear receptors in liver. These relatively high dose and long term exposures to triazole antifungals appeared to perturb fatty acid and steroid metabolism in the rat liver predominantly through the CAR and PXR signaling pathways. These toxicogenomic effects serve as biomarkers of a plausible series of key events contributing to the disruption in steroid homeostasis and reproductive toxicity of the triazole antifungals.
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Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals