ToxSci Advance Access published online on March 22, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm065
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Published by Oxford University Press 2007.
Toxicogenomic Study of Triazole Fungicides and Perfluoroalkyl Acids in Rat Livers Predicts Toxicity and Categorizes Chemicals Based on Mechanisms of Toxicity
1 Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA 2 Iconix Biosciences, Mountain View, CA 94043, USA
* Address for correspondence: David J. Dix, National Center for Computational Toxicology (D343-03), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 USA, Telephone: (919)541-2701, Fax: (919)541-1194, Email: dix.david{at}epa.gov
Received October 24, 2006; revision received March 16, 2007; accepted March 20, 2007
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Abstract |
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Toxicogenomic analysis of five environmental chemicals was performed to investigate the ability of genomics to predict toxicity, categorize chemicals and elucidate mechanisms of toxicity. Three triazole antifungals (myclobutanil, propiconazole and triadimefon) and two perfluorinated chemicals (perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS)) were administered daily via oral gavage for 1, 3, or 5 consecutive days to male Sprague-Dawley rats at single doses of 300, 300, 175, 20, or 10 mg/kg/d, respectively. Clinical chemistry, hematology and histopathology were measured at all time points. Gene expression profiling of livers from 3 rats per treatment group at all time points was performed on the CodeLink RU1 rat array. Data were analyzed in the context of a large reference toxicogenomic database containing gene expression profiles for over 630 chemicals. Genomic signatures predicting hepatomegaly and hepatic injury preceded those results for all five chemicals and further analysis segregated chemicals into two distinct classes. The triazoles caused similar gene expression changes as other azole antifungals, particularly the induction of PXR (pregnane X receptor)-regulated xenobiotic metabolism and oxidative stress genes. In contrast, PFOA and PFOS exhibited PPAR
(peroxisome proliferator-activated receptor alpha) agonist-like effects on genes associated with fatty-acid homeostasis. PFOA and PFOS also resulted in downregulation of cholesterol biosynthesis genes, matching an in vivo decrease in serum cholesterol, and perturbation of thyroid hormone metabolism genes matched by serum thyroid hormone depletion in vivo. The concordance of in vivo observations and gene expression findings demonstrated the ability of genomics to accurately categorize chemicals, identify toxic mechanisms of action, and predict subsequent pathological responses.
Key Words: myclobutanil; propiconazole; triadimefon; PFOA; PFOS; genomic signatures.
Disclaimer: The information in this document has been funded wholly by the EPA. This work was reviewed by EPA and approved for publication but does not necessarily reflect official Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation by EPA for use.
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