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ToxSci Advance Access published online on April 7, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh130
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received December 18, 2003; accepted March 10, 2004
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.

Systems Evaluation

trans-Activation of PPAR{alpha} and Induction of PPAR{alpha} Target Genes by Perfluorooctane-Based Chemicals

Jonathan M. Shipley 1, Christopher H. Hurst 1, Sue S. Tanaka 2, Fred L. DeRoos 3, John L. Butenhoff 2, Andrew M. Seacat 2, and David J. Waxman 1*

1 Division of Cell and Molecular Biology, Department of Biology, Boston University, 5 Cummington St., Boston MA 02215
2 3M Medical Department, Corporate Toxicology, 3M Center 220-2E-02, Maplewood MN 55144
3 3M Corporate Research Analytical Laboratory, 3M Center 201-1W-29, Maplewood, MN 55144

* To whom correspondence should be addressed. E-mail: djw{at}bu.edu.


  Abstract

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{alpha} 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{alpha}. The present study investigates this question and characterizes the activation of mouse and human PPAR{alpha} by PFOSAs. Perfluorooctanesulfonate (PFOS), an end-stage metabolite common to several PFOSAs, was found to activate both mouse and human PPAR{alpha} 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{alpha}. Mouse and human PPAR{alpha} 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 ethyl alcohol were less informative due to its insolubility. These findings were verified in an FAO rat hepatoma cell line that stably expresses PPAR{alpha}, where the endogenous PPAR{alpha} 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{alpha} 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 perfluorochemicals.


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