ToxSci Advance Access originally published online on May 26, 2006
Toxicological Sciences 2006 92(2):476-489; doi:10.1093/toxsci/kfl014
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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-
, -ß, and -
, Liver X Receptor-ß, and Retinoid X Receptor-
,
* Department of Veterinary and Biomedical Science and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802; DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware 19714; and Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802
Received March 24, 2006; accepted May 1, 2006
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-
(PPAR). Due to its fatty acid structure, PFOA may activate other NRs, such as PPARß, PPAR
, liver X receptor (LXR), or retinoid X receptor (RXR). In this study, the activation of human, mouse, and rat PPAR, PPARß, PPAR, LXRß, and RXR 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 PPAR were activated by PFOA isomers and PFOS. PPARß was less sensitive to the agents tested, with only PFOA affecting the mouse receptor. PFOA and PFOS also activated human, mouse, and rat PPAR, although the maximum induction of PPAR was much less than that seen with rosiglitazone, suggesting that PFOA and PFOS are partial agonists of this receptor. Neither LXRß nor the common heterodimerization partner RXR was activated by PFOA in any species examined. Taken together, these data show that of the NRs studied, PPAR is the most likely target of PFOA and PFOS, although PPAR is also activated to some extent. Compared to naturally occurring long-chain fatty acids, e.g. linoleic and -linolenic acids, these perfluorinated fatty acid analogs were more selective and less potent in their activation of the NRs.
Key Words: nuclear receptors; transactivation; dietary fatty acids; fatty acid analogs.
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