Differential Activation of Nuclear Receptors by Perfluorinated Fatty Acid Analogs and Natural Fatty Acids: A Comparison of Human, Mouse, and Rat Peroxisome Proliferator-Activated Receptor-α, -β, and -γ, Liver X Receptor-β, and Retinoid X Receptor-α

Abstract

Administration of ammonium salts of perfluorooctanoate (PFOA) to rats results in peroxisome proliferation and benign liver tumors, events associated with activation of the nuclear receptor (NR) peroxisome proliferator-activated receptor-alpha (PPARalpha). Due to its fatty acid structure, PFOA may activate other NRs, such as PPARbeta, PPARgamma, liver X receptor (LXR), or retinoid X receptor (RXR). In this study, the activation of human, mouse, and rat PPARalpha, PPARbeta, PPARgamma, LXRbeta, and RXRalpha by PFOA (including its linear and branched isomers) and perfluorooctane sulfonate (PFOS) was investigated and compared to several structural classes of natural fatty acids and appropriate positive control ligands. An NR ligand-binding domain/Gal4 DNA-binding domain chimeric reporter system was used. Human, mouse, and rat PPARalpha were activated by PFOA isomers and PFOS. PPARbeta was less sensitive to the agents tested, with only PFOA affecting the mouse receptor. PFOA and PFOS also activated human, mouse, and rat PPARgamma, although the maximum induction of PPARgamma was much less than that seen with rosiglitazone, suggesting that PFOA and PFOS are partial agonists of this receptor. Neither LXRbeta nor the common heterodimerization partner RXRalpha was activated by PFOA in any species examined. Taken together, these data show that of the NRs studied, PPARalpha is the most likely target of PFOA and PFOS, although PPARgamma is also activated to some extent. Compared to naturally occurring long-chain fatty acids, e.g. linoleic and alpha-linolenic acids, these perfluorinated fatty acid analogs were more selective and less potent in their activation of the NRs.

Interaction of perfluoroalkyl acids with human liver fatty acid-binding protein

“…PFAAs (n > 8) can activate PPAR activators (PPARα and PPARγ), as well as the constitutive androstane receptor and pregnane X receptor (Ding et al 2009;Fang et al 2012;Vanden Heuvel et al 2006). As these nuclear hormone receptors are located in the nucleus of the hepatocyte, transport of these relatively insoluble lipophilic environmental pollutants from the cytoplasm to the nucleus seems to be required for activation of the PPARs transcriptional response.…”

Historical Trends in Human Serum Levels of Perfluorooctanoate and Perfluorooctane Sulfonate in Shenyang, China

“…At the cellular and molecular levels, these chemicals are classified as peroxisomal proliferators (Vanden Heuvel et al 2006). The mechanisms of their toxicities, other than in fatty acid metabolism, are not fully understood.…”

Perfluorooctanoic acid binds to peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation in 3T3-L1 adipocytes

“…21,22) Increased PPAR α activity results in fat utilization and a subsequent reduction in BW. Further studies are needed to examine the potential of PFOA as an obesogen from various aspects.…”