title: The hepatocarcinogenic conazoles: cyproconazole, epoxiconazole, and propiconazole induce a common set of toxicological and transcriptional responses.
abstract: Conazoles are fungicides used as agricultural pesticides and pharmaceutical products. We investigated whether a common core of toxicological and transcriptional responses underlies the observed carcinogenic effects of three conazoles: cyproconazole, epoxiconazole, and propiconazole. In studies where mice were fed diets of these conazoles for 30 days, we found a common set of toxicological effects altered by these conazoles: hepatomegaly, hepatocellular hypertrophy, decreased serum cholesterol, decreased hepatic levels of all-trans-retinoic acid, and increased hepatic cell proliferation. Microarray-based transcriptional analysis revealed 330 significantly altered probe sets common to these conazoles, many of which showed strong dose responses for cytochrome P450, glutathione S-transferase, and oxidative stress genes. More detailed analyses identified a subset of 80 altered genes common to the three conazoles that were associated with cancer. Pathways associated with these genes included xenobiotic metabolism, oxidative stress, cell signaling, and cell proliferation. A common TGFα-centric pathway was identified within the 80-gene set, which, in combination with the toxicological and other transcriptomic findings, provides a more refined toxicity profile for these carcinogenic conazoles.
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. hester.susan@epa.gov
authors.forename: Susan
authors.initials: S
authors.lastname: Hester
authors.forename: Tanya
authors.initials: T
authors.lastname: Moore
authors.forename: William T
authors.initials: WT
authors.lastname: Padgett
authors.forename: Lynea
authors.initials: L
authors.lastname: Murphy
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wood
authors.forename: Stephen
authors.initials: S
authors.lastname: Nesnow
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000633:toxicity; D005659:Fungicides, Industrial / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D004852:Epoxy Compounds; D005659:Fungicides, Industrial; D016211:Transforming Growth Factor alpha; D014230:Triazoles; C045950:propiconazole; C093628:cyproconazole; C109476:epoxiconazole