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-a, -b, and -c, Liver X Receptor-b, and Retinoid X Receptor-a

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-a (PPARa). Due to its fatty acid structure, PFOA may activate other NRs, such as PPARb, PPARg, liver X receptor (LXR), or retinoid X receptor (RXR). In this study, the activation of human, mouse, and rat PPARa, PPARb, PPARg, LXRb, and RXRa 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 PPARa were activated by PFOA isomers and PFOS. PPARbwas less sensitive to the agents tested, with only PFOA affecting the mouse receptor. PFOA and PFOS also activated human, mouse, and rat PPARg, although the maximum induction of PPARg was much less than that seen with rosiglitazone, suggesting that PFOA and PFOS are partial agonists of this receptor. Neither LXRb nor the common heterodimerization partner RXRa was activated by PFOA in any species examined. Taken together, these data show that of the NRs studied, PPARa is the most likely target of PFOA and PFOS, although PPARg is also activated to some extent. Compared to naturally occurring long-chain fatty acids, e.g. linoleic and alinolenic acids, these perfluorinated fatty acid analogs were more selective and less potent in their activation of the NRs.