ABSTRACT: The triazole antifungals myclobutanil (MYC), propiconazole (PPZ) and triadimefon (TDF) [Propiconazole CASNR 60207-90-1; Triadimefon CASNR 43121-43-3; Myclobutanil CASNR 88671-89-0] all disrupt steroid hormone homeostasis and cause varying degrees of hepatic toxicity. To identify biological pathways consistently activated across various study designs, gene expression profiling was conducted on livers from rats following acute, repeated dose, or prenatal to adult exposures. To explore conservation of responses across species, gene expression from these rat in vivo studies were also compared to in vitro data from rat and human primary hepatocytes exposed to MYC, PPZ, or TDF. Pathway and gene level analyses across time of exposure, dose, and species identified patterns of expression common to all three triazoles, which were also conserved between rodents and humans. Pathways affected included androgen and estrogen metabolism, xenobiotic metabolism signaling through CAR and PXR, and CYP mediated metabolism. Many of the differentially expressed genes are regulated by the nuclear receptors CAR, PPAR alpha and PXR, including ABC transporter genes (Abcb1 and MDR1), genes significant to xenobiotic, fatty acid, sterol and steroid metabolism (Cyp2b2 and CYP2B6; Cyp3a1 and CYP3A4; Cyp4a22 and CYP4A11) and xxx (Ugt1a1 and UGT1A1). Modulation of hepatic sterol and steroid metabolism is a plausible mechanism for triazole induced increases in serum testosterone. The gene expression changes caused by all three triazoles appear to focus on pathways regulating lipid and testosterone homeostasis, identifying potential common mechanisms of triazole hepatotoxicity that are conserved between rodents and humans. Experiment Overall Design: A total of 43 samples were analyzed. Four biological replicates for the controls (DMSO 0.1%), 2 biological replicates for positive control Rifampicin CASNR 13292-46-1, 4 biological replicates for positive control Phenobarbital sodium CASNR 57-30-7, 3 biological replicates for low dose myclobutanil, 3 biological replicates for mid dose myclobutanil, 4 biological replicates for high dose myclobutanil. Four biological replicates each for low, mid, and high dose propiconazole, and 4, 4, and 3 biological replicates each for low, mid, and high dose triadimefon, respectively.
