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
PPARalpha 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
PPARalpha. The present study investigates this question and characterizes the activation of mouse and human
PPARalpha by PFOSAs.
Perfluorooctanesulfonate (PFOS), an end-stage metabolite common to several PFOSAs, was found to activate both mouse and human
PPARalpha in a COS-1 cell-based
luciferase reporter trans-activation assay. Half-maximal activation (EC50) occurred at 13-15 microM PFOS, with no significant difference in the responsiveness of mouse and human
PPARalpha. Mouse and human
PPARalpha 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
PPARalpha, where the endogenous
PPARalpha target genes
peroxisomal bifunctional enzyme and peroxisomal 3-ketoacyl-CoA thiolase were activated up to approximately 10-20-fold by PFOS and FOSA. The interactions of
PPARalpha 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.