ToxSci Advance Access originally published online on May 7, 2009
Toxicological Sciences 2009 110(2):449-462; doi:10.1093/toxsci/kfp098
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Published by Oxford University Press 2009.
Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals
* National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695
1 To whom correspondence should be addressed at National Center for Computational Toxicology, Mail Drop D343-03, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-1194. E-mail: dix.david{at}epa.gov.
Received January 16, 2009; accepted April 21, 2009
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Abstract |
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The mode of action for the reproductive toxicity of some triazole antifungals has been characterized as an increase in serum testosterone and hepatic response, and reduced insemination and fertility indices. In order to refine our mechanistic understanding of these potential modes of action, gene expression profiling was conducted on liver and testis from male Wistar Han IGS rats exposed to myclobutanil (500, 2000 ppm), propiconazole (500, 2500 ppm), or triadimefon (500, 1800 ppm) from gestation day six to postnatal day 92. Gene expression profiles indicated that all three triazoles significantly perturbed the fatty acid, steroid, and xenobiotic metabolism pathways in the male rat liver. In addition, triadimefon modulated expression of genes in the liver from the sterol biosynthesis pathway. Although expression of individual genes were affected, 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 form part of a network involving lipid, sterol, and steroid homeostatic pathways regulated by the constitutive androstane (CAR), pregnane X (PXR), peroxisome proliferator–activated alpha, 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 male rat liver predominantly through the CAR and PXR signaling pathways. These toxicogenomic effects describe a plausible series of key events contributing to the disruption in steroid homeostasis and reproductive toxicity of select triazole antifungals.
Key Words: myclobutanil; propiconazole; triadimefon; toxicogenomics; steroid metabolism.
Disclaimer: The United States Environmental Protection Agency through its Office of Research and Development funded and managed the research described here. It has been subjected to Agency administrative review and approved for publication.