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-
beta-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.