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Propiconazole induces alterations in the hepatic metabolome of mice: relevance to propiconazole-induced hepatocarcinogenesis
Citation:
NESNOW, S., T. MOORE, AND W. PADGETT. Propiconazole induces alterations in the hepatic metabolome of mice: relevance to propiconazole-induced hepatocarcinogenesis. Presented at Society of Toxicology (SOT) Annual Meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
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
Description:
Propiconazole is a mouse hepatotumorigenic fungicide and has been the subject of recent mechanistic investigations on 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-l mice in the feed for 4 days with 6 mice per group (500, 1250, and 2500 ppm). Endogenous biochemicals were profiled using LC-MS/MS and GCMS 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 may showed strong dose responses. Many alterations in the levels of biochemicals were found in the glycogen metabolism, glycolysis, lipolysis, camitine 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 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 polyamine and sarcosine biosynthesis, and increases in pseudouridine levels. These results extended the companion transcriptomic and proteomic studies and provided a more complete picture of propiconazole's effects in mouse liver. This work was reviewed by EPA and approved for publication but does not necessarily reflect official Agency policy.