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DOI: 10.1080/01926230601047832 © 2006 Society of Toxicologic Pathology
Transcriptional Profiles in Liver from Mice Treated with Hepatotumorigenic and Nonhepatotumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and MyclobutanilEnvironmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA Correspondence: Address correspondence to: William O. Ward, Cancer Biology Branch, Environmental Carcinogenesis Division, U. S. Environmental Protection Agency, B143-06, 109 TW Alexander Drive, Research Triangle Park, NC 27711, USA; e-mail:ward.william{at}epa.gov Conazoles are environmental and pharmaceutical fungicides. The present study relates the toxicological effects of conazoles to alterations of gene and pathway transcription and identifies potential modes of tumorigenic action. In a companion study employing conventional toxicological bioassays (Allen et al., 2006), male CD-1 mice were fed triadimefon, propiconazole, or myclobutanil in a continuous oral-dose regimen for 4, 30, or 90 days. These conazoles were found to induce hepatomegaly, to induce high levels of hepatic pentoxyresorufin-O-dealkylase activity, to increase hepatic cell proliferation, to decrease serum cholesterol, and to increase serum triglycerides. Differentially expressed genes and pathways were identified using Affymetrix GeneChips. Gene-pathway associations were obtained from the Kyoto Encyclopedia of Genes and Genomes, Biocarta, and MetaCore compendia. The pathway profiles of each conazole were different at each time point. In general, the number of altered metabolism, signaling, and growth pathways increased with time and dose and were greatest with propiconazole. All conazoles had effects on nuclear receptors as evidenced by increased expression and enzymatic activities of a series of related cytochrome P450s (CYP). A subset of altered genes and pathways distinguished the three conazoles from each other. Triadimefon and propiconazole both altered apoptosis, cell cycle, adherens junction, calcium signaling, and EGFR signaling pathways. Triadimefon produced greater changes in cholesterol biosynthesis and retinoic acid metabolism genes and in selected signaling pathways. Propiconazole had greater effects on genes responding to oxidative stress and on the IGF/P13K/AKt/PTEN/mTor and Wnt-β-catenin pathways. In conclusion, while triadimefon, propiconazole, and myclobutanil had similar effects in mouse liver on hepatomegaly, histology, CYP activities, cell proliferation, and serum cholesterol, genomic analyses revealed major differences in their gene expression profiles.
Key Words: Conazoles • triadimefon • propiconazole • myclobutanil • mouse liver • genomic profiles • tumorigenesis Abbreviations: ANOVA, analysis of variance • CYP, cytochrome P450 • DEG, differentially expressed gene • EPA, Environmental Protection Agency • FDR, false discovery rate • KEGG, Kyoto Encyclopedia of Genes and Genomes • LXR, liver X-activated receptor • PCA, principal component analysis • ppm, parts per million • RXR, 9-cis retinoic acid receptor
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