trans-Activation of PPARa and Induction of PPARa Target Genes by Perfluorooctane-Based Chemicals

Peroxisome proliferator-activated receptors (PPARs) are liganddependent transcription factors that activate target genes involved in lipid metabolism, energy homeostasis, and cell differentiation in response todiverse compounds, includingenvironmental chemicals. The liver-expressed receptor PPARa 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 PPARa. The present study investigates this question and characterizes the activation of mouse and human PPARa by PFOSAs. Perfluorooctanesulfonate (PFOS),anend-stagemetabolite commontoseveral PFOSAs, was found to activate bothmouse and human PPARa in a COS-1 cell-based luciferase reporter trans-activation assay. Halfmaximal activation (EC50) occurred at 13–15 mM PFOS, with no significant difference in the responsiveness of mouse and human PPARa. Mouse and human PPARa 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 PPARa, where the endogenous PPARa target genes peroxisomal bifunctional enzyme andperoxisomal 3-ketoacyl-CoA thiolasewere activatedup to 10–20-foldbyPFOSandFOSA.The interactions of PPARawith 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 andmay aid in the evaluation of human and environmental risks associated with exposure to this important class of fluorochemicals.