The hepatocarcinogenic conazoles: cyproconazole, epoxiconazole, and propiconazole induce a common set of toxicological and transcriptional responses

Toxicol Sci. 2012 May;127(1):54-65. doi: 10.1093/toxsci/kfs086. Epub 2012 Feb 14.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Carcinogens / toxicity*
  • Cell Proliferation / drug effects
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Dose-Response Relationship, Drug
  • Epoxy Compounds / toxicity
  • Fungicides, Industrial / toxicity*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Liver / drug effects
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Oligonucleotide Array Sequence Analysis
  • Transforming Growth Factor alpha / genetics
  • Transforming Growth Factor alpha / metabolism
  • Triazoles / toxicity*

Substances

  • Carcinogens
  • Epoxy Compounds
  • Fungicides, Industrial
  • Transforming Growth Factor alpha
  • Triazoles
  • propiconazole
  • cyproconazole
  • epoxiconazole