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

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 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.

Effects of elevated dissolved carbon dioxide and perfluorooctane sulfonic acid, given singly and in combination, on steroidogenic and biotransformation pathways of Atlantic cod

“…Several nuclear receptors have been suggested to affect estrogenic gene expression. Among these are peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) that were affected by PFOS Fang et al, 2012;Shi et al, 2009;Shipley et al, 2004). The present findings are in accordance with other studies indicating estrogenic effects of PFOS in teleost species, demonstrating altered, and mostly elevated expression of estrogen responsive genes (Du et al, 2009;Fang et al, 2012;Keiter et al, 2012;Liu et al, 2007).…”

The induction of atherogenic dyslipidaemia in poloxamer 407-treated mice is not mediated through PPARα

“…Male, PPARα-knockout mice (∼18 g) were purchased from the Jackson Laboratory (strain name = 129S4/SvJaePpara tm1Gonz /J). Plasmids were obtained from the same sources as previously reported (Maloney & Waxman 1999;Shipley et al 2004a;Shipley & Waxman 2004b).…”

“…The transactivation assay described previously (Maloney & Waxman 1999;Shipley et al 2004a;Shipley & Waxman 2004b) was used to assess the effect of P-407 on PPARα transcriptional activity. Briefly, COS-1 cells (American Type Culture Collection, Rockville, MD) were passaged in 100-mm tissue culture dishes (Greiner Labortechnik, Germany) in DMEM supplemented with 10% FBS (Gibco, Grand Island, NY) and 50 U/mL penicillin/ streptomycin (Gibco).…”

Activation of peroxisome proliferator-activated receptor α ameliorates perfluorododecanoic acid-induced production of reactive oxygen species in rat liver

“…Studies have shown that exposure to PFASs can also induce lower serum glucose levels, lower cholesterol levels and higher β-oxidation of fatty acids as well as induce adenoma in hepatocytes (Lau et al 2007;Seacat et al 2003;Shipley et al 2004). However, the mode of action related to PFAS toxicity in rodents is not fully understood.…”