Transcriptional Profiles in Liver from Mice Treated with Hepatotumorigenic and Nonhepatotumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

Abstract

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.

Hepatotoxic effects of (tri)azole fungicides in a broad dose range

“…To meet these demands, here, a 28-day feeding study in the rat was conducted with three substances (cyproconazole, epoxiconazole and prochloraz) in a broad dose range conceiving a typical toxicological threshold level (based on a nOAeL derived from a regulatory guideline study divided by a safety factor of 100) up to a clear effect dose (nOAeLx10). The study protocol was based on a regulatory guideline (OecD Tg407), but additional molecular methods were performed, including toxicity pathway-focused low-density gene expression arrays with subsets of marker genes previously identified as triazole related (goetz and Dix 2009b;Tully et al 2006;Ward et al 2006). here, we report the results of this study.…”

Toxicity Profiles in Mice Treated with Hepatotumorigenic and Non-Hepatotumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil

“…This work is part of a larger toxicogenomic study (Ward et al, 2006) aimed at determining the mode(s) of action for these selected hepatotumorigenic conazoles.…”

The glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 has broad substrate specificity: Physiological and toxicological considerations

“…Conazoles exert their effect by inhibition of the fungal lanosterol-14R-demethylase CYP51, thereby blocking the biosynthesis of ergosterol, an essential element of fungal cell membranes. Several toxic effects of conazoles have been observed in mammalian systems, including activation of nuclear receptors (CAR, PXR and PPAR) and induction of CYPs [168]. Kenneke et al reported a dose-dependent inhibition of the conversion of triadimefon to triadimefol by glycyrrhetinic acid with an IC 50 of 31 nM [167].…”