title: Transcriptional profiles in liver from rats treated with tumorigenic and non-tumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil.
abstract: Conazoles are a class of fungicides used as pharmaceutical and agricultural agents. In chronic bioassays in rats, triadimefon was hepatotoxic and induced follicular cell adenomas in the thyroid gland, whereas, propiconazole and myclobutanil were hepatotoxic but had no effect on the thyroid gland. These conazoles administered in the feed to male Wistar/Han rats were found to induce hepatomegaly, induce high levels of pentoxyresorufin-O-dealkylase, increase cell proliferation in the liver, increase serum cholesterol, decrease serum T3 and T4, and increase hepatic uridine diphosphoglucuronosyl transferase activity. The goal of the present study was to define pathways that explain the biologic outcomes. Male Wistar/Han rats (3 per group), were exposed to the 3 conazoles in the feed for 4, 30, or 90 days of treatment at tumorigenic and nontumorigenic doses. Hepatic gene expression was determined using high-density Affymetrix GeneChips (Rat 230_2). Differential gene expression was assessed at the probe level using Robust Multichip Average analysis. Principal component analysis by treatment and time showed within group sample similarity and that the treatment groups were distinct from each other. The number of altered genes varied by treatment, dose, and time. The greatest number of altered genes was induced by triadimefon and propiconazole after 90 days of treatment, while myclobutanil had minimal effects at that time point. Pathway level analyses revealed that after 90 days of treatment the most significant numbers of altered pathways were related to cell signaling, growth, and metabolism. Pathway level analysis for triadimefon and propiconazole resulted in 71 altered pathways common to both chemicals. These pathways controlled cholesterol metabolism, activation of nuclear receptors, and N-ras and K-ras signaling. There were 37 pathways uniquely changed by propiconazole, and triadimefon uniquely altered 34 pathways. Pathway level analysis of altered gene expression resulted in a more complete description of the associated toxicological effects that can distinguish triadimefon from propiconazole and myclobutanil.
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. hester.susan@epa.gov
authors.forename: Susan D
authors.initials: SD
authors.lastname: Hester
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wolf
authors.forename: Stephen
authors.initials: S
authors.lastname: Nesnow
authors.forename: Sheau-Fung
authors.initials: SF
authors.lastname: Thai
mesh_terms: D000818:Animals; D001681:Biological Assay; D002453:Cell Cycle / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005659:Fungicides, Industrial / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D009570:Nitriles / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013963:Thyroid Hormones / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D014230:Triazoles / Q000633:toxicity*
chemical_list: D005659:Fungicides, Industrial; D008055:Lipids; D009570:Nitriles; D013963:Thyroid Hormones; D014230:Triazoles; C045950:propiconazole; C032910:triadimefon; D012313:RNA; D002784:Cholesterol; C446685:systhane