ToxSci Advance Access originally published online on April 7, 2004
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Toxicological Sciences 80, 151-160 (2004)
Toxicological Sciences vol. 80 no. 1 © Society of Toxicology 2004; all rights reserved.
trans-Activation of PPAR
and Induction of PPAR Target Genes by Perfluorooctane-Based Chemicals
* Division of Cell and Molecular Biology, Department of Biology, Boston University, 5 Cummington Street, Boston, Massachusetts 02215; 3M Medical Department, Corporate Toxicology, 3M Center 220-2E-02, Maplewood, Minnesota 55144; and 3M Corporate Research Analytical Laboratory, 3M Center 201-1W-29, Maplewood, Minnesota 55144
Received December 18, 2003; accepted March 8, 2004
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that activate target genes involved in lipid metabolism, energy homeostasis, and cell differentiation in response to diverse compounds, including environmental chemicals. The liver-expressed receptor PPAR
mediates peroxisome proliferative responses associated with rodent hepatocarcinogenesis. Previous studies have established that certain perfluorooctanesulfonamide-based chemicals (PFOSAs) alter lipid metabolism, are hepatic peroxisome proliferators, and induce hepatocellular adenoma formation in rodents, suggesting that they activate PPAR. The present study investigates this question and characterizes the activation of mouse and human PPAR by PFOSAs. Perfluorooctanesulfonate (PFOS), an end-stage metabolite common to several PFOSAs, was found to activate both mouse and human PPAR in a COS-1 cell-based luciferase reporter trans-activation assay. Half-maximal activation (EC50) occurred at 13–15 µM PFOS, with no significant difference in the responsiveness of mouse and human PPAR. Mouse and human PPAR were activated by perfluorooctanesulfonamide (FOSA) over a similar concentration range; however, cellular toxicity precluded an accurate determination of EC50 values. Studies of 2-N-ethylperfluorooctanesulfonamido ethanol were less informative due to its insolubility. These findings were verified in an FAO rat hepatoma cell line that stably expresses PPAR, where the endogenous PPAR target genes peroxisomal bifunctional enzyme and peroxisomal 3-ketoacyl-CoA thiolase were activated up to 
10–20-fold by PFOS and FOSA. The interactions of PPAR with PFOS and FOSA, and the potential of these chemicals for activation of unique sets of downstream target genes, may help explain the diverse biological effects exhibited by PFOSAs and may aid in the evaluation of human and environmental risks associated with exposure to this important class of fluorochemicals.
Key Words: perfluorooctanesulfonamide; perfluorooctanesulfonate; N-ethyl perfluorooctanesulfonamidoethanol; rodenthepatocarcinogenesis; ppar; peroxisome proliferation.
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