title: 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.
authors.affiliation: Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. allen.james@epa.gov
authors.forename: James W
authors.initials: JW
authors.lastname: Allen
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wolf
authors.forename: Michael H
authors.initials: MH
authors.lastname: George
authors.forename: Susan D
authors.initials: SD
authors.lastname: Hester
authors.forename: Guobin
authors.initials: G
authors.lastname: Sun
authors.forename: Sheau-Fung
authors.initials: SF
authors.lastname: Thai
authors.forename: Don A
authors.initials: DA
authors.lastname: Delker
authors.forename: Tanya
authors.initials: T
authors.lastname: Moore
authors.forename: Carlton
authors.initials: C
authors.lastname: Jones
authors.forename: Gail
authors.initials: G
authors.lastname: Nelson
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Roop
authors.forename: Sharon
authors.initials: S
authors.lastname: Leavitt
authors.forename: Ernest
authors.initials: E
authors.lastname: Winkfield
authors.forename: William O
authors.initials: WO
authors.lastname: Ward
authors.forename: Stephen
authors.initials: S
authors.lastname: Nesnow
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D002273:Carcinogens; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D009570:Nitriles / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D014230:Triazoles / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D005659:Fungicides, Industrial; D008055:Lipids; D008075:Lipoproteins, HDL; D009570:Nitriles; D014230:Triazoles; C045950:propiconazole; C032910:triadimefon; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; C446685:systhane