Journal Article

The Hepatocarcinogenic Conazoles: Cyproconazole, Epoxiconazole, and Propiconazole Induce a Common Set of Toxicological and Transcriptional Responses

Susan Hester, Tanya Moore, William T. Padgett, Lynea Murphy, Charles E. Wood and Stephen Nesnow

in Toxicological Sciences

Volume 127, issue 1, pages 54-65
Published in print May 2012 | ISSN: 1096-6080
Published online February 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs086
The Hepatocarcinogenic Conazoles: Cyproconazole, Epoxiconazole, and Propiconazole Induce a Common Set of Toxicological and Transcriptional Responses

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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.

Keywords: conazoles; cyproconazole; epoxiconazole; propiconazole; transcriptional analyses; hepatocarcinogenic; cell proliferation; liver; mice; all-trans-retinoic acid; cholesterol; Ki67

Journal Article.  7161 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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