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Propiconazole induces alterations in the hepatic metabolome of mice: relevance to propiconazole-induced hepatocarcinogenesis
Citation:
NESNOW, S. Propiconazole induces alterations in the hepatic metabolome of mice: relevance to propiconazole-induced hepatocarcinogenesis. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 120(2):297-309, (2011).
Impact/Purpose:
The impact of this paper in the application and use of toxicogenomics (transcriptomics, proteomics and metabolomics) in supporting and defining a mode of action for propiconazole, a prototype for a class of environmental fungicides. OCSPP has requested research on conazoles that could support future risk assessments of conazoles and other pesticidal agents. This research is a compendium ofbiochemical, molecular, mutational and toxicogenomic studies aimed at improving future risk assessments
Description:
Propiconazole is a mouse hepatotumorigenic fungicide and has been the subject of recent investigations into its carcinogenic mechanism of action. The goals of this study were: 1. To identify metabolomic changes induced in the liver by increasing doses of propiconazole in mice; 2. To interpret these results with key previously reported biochemical, transcriptomic and proteomic findings obtained from mouse liver under the same treatment conditions; 3. To relate these alterations to those associated with the carcinogenesis process. Propiconazole was administered to male CD-1 mice in the feed for 4 days with 6 mice per feed level (500, 1250, and 2500 ppm). The 2500 ppm dose level had previously been shown to induce both adenocarcinomas and adenomas in mouse liver after a 2-yr continuous feed regimen. Endogenous biochemicals were profiled using LC-MS/MS and GC-MS methods and 261 were detected. The most populous biochemical class detected was lipids, followed by amino acids and then carbohydrates. Nucleotides, cofactors and vitamins, energy, peptides and xenobiotics were also represented. Of the biochemicals detected 159 were significantly altered by at least one dose of propiconazole and many showed strong dose responses. Many alterations in the levels of biochemicals were found in the glycogen metabolism, glycolysis, lipolysis, carnitine and the TCA cycle pathways. Several groups of metabolomic responses were ascribed to the metabolism and clearance of propiconazole: glucuronate, glutathione and cysteine pathways. Groups of metabolic responses supported previous hypotheses on key events that can lead to propiconazole induced tumorigenesis: oxidative stress and increases in the cholesterol biosynthesis pathway. Groups of metabolomic responses identified biomarkers associated with neoplasia: increases in glycolysis and increases in the levels of spermidine, sarcosine, and pseudouridine. These results extended the companion transcriptomic and proteomic studies and provided a more complete understanding of propiconazole's effects in mouse liver.
