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

Abstract

Conazoles comprise a class of fungicides used in agriculture and as pharmaceutical products. The fungicidal properties of conazoles are due to their inhibition of ergosterol biosynthesis. Certain conazoles are tumorigenic in rodents; both propiconazole and triadimefon are hepatotoxic and hepatotumorigenic in mice, while myclobutanil is not a mouse liver tumorigen. As a component of a large-scale study aimed at determining the mode(s) of action for tumorigenic conazoles, we report the results from comparative evaluations of liver and body weights, liver histopathology, cell proliferation, cytochrome P450 (CYP) activity, and serum cholesterol, high-density lipoprotein and triglyceride levels after exposure to propiconazole, triadimefon, and myclobutanil. Male CD-1 mice were treated in the feed for 4, 30, or 90 days with triadimefon (0, 100, 500, or 1800 ppm), propiconazole (0, 100, 500, or 2500 ppm) or myclobutanil (0, 100, 500, or 2000 ppm). Alkoxyresorufin O-dealkylation (AROD) assays indicated that all 3 chemicals induced similar patterns of dose-related increases in metabolizing enzyme activity. PROD activities exceeded those of MROD, and EROD with propiconazole inducing the highest activities of PROD. Mice had similar patterns of dose-dependent increases in hepatocyte hypertrophy after exposure to the 3 conazoles. High-dose exposures to propiconazole and myclobutanil, but not triadimefon, were associated with early (4 days) increases in cell proliferation. All the chemicals at high doses reduced serum cholesterol and high-density lipoprotein (HDL) levels at 30 days of treatment, while only triadimefon had this effect at 4 days of treatment and only myclobutanil and propiconazole at 90 days of treatment. Overall, the tumorigenic and nontumorigenic conazoles induced similar effects on mouse liver CYP enzyme activities and pathology. There was no specific pattern of tissue responses that could consistently be used to differentiate the tumorigenic conazoles, propiconazole, and triadimefon, from the nontumorigenic myclobutanil. These findings serve to anchor other transcriptional profiling studies aimed at probing differences in key events and modes of action for tumorigenic and nontumorigenic conazoles.

Comparative Hepatic Effects of Perfluorooctanoic Acid and WY 14,643 in PPAR-α Knockout and Wild-type Mice

“…The fixed livers were processed by routine methods for paraffin section and staining with hematoxylin and eosin (HE) for light microscopic examination or for epon embedment; they were then sectioned for uranyl acetate staining and ultrastructural examination by transmission electron microscopy. In addition to the HE-stained section, a companion paraffin section was processed for immunohistochemistry of proliferating cell nuclear antigen (PCNA) (Allen et al 2006).…”

“…A Cytology/Histology Recognition Information System (CHRIS, Sverdrup Technology, Inc., Ft. Walton Beach, FL) was used to quantitate the LI from PCNA stained slides. Each image was examined and edited for accuracy (Allen et al 2006;Medinsky et al 1999). All liver slides were evaluated for LI without knowledge of treatment.…”

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

“…The complete details and results of the in-life experiments are described in Allen et al (2006) and this study provided the liver tissues used in the current study. Briefly in the Allen et al (2006) study, male CD-1 mice received triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), myclobutanil (100, 500, 2000 ppm) or vehicle-treated feed for 4, 30, and 90 days.…”

“…Based on the lack of genotoxicity, and increases in liver hypertrophy, Cyp2b20(10) induction, and cell proliferation, it has been proposed that the tumorigenic mode of action of fenbuconazole in mice is similar to that of phenobarbital (Juberg et al, 2006). An accompanying paper (Allen et al, 2006) describes inlife studies in mice with triadimefon, propiconazole, and myclobutanil in which traditional toxicity endpoints were evaluated. The present analyses of conazole-altered gene expression represent an extension of these studies aimed at the identification of potential modes(s) of tumorigenic action.…”

“…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.…”