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-alpha, -beta, and -gamma, liver X receptor-beta, and retinoid X receptor-alpha

Vanden Heuvel, J.P.; Thompson, J.T.; Frame, S.R.; Gillies, P.J.

Toxicological Sciences An Official Journal of the Society of Toxicology 92(2): 476-489

2006


ISSN/ISBN: 1096-6080
PMID: 16731579
DOI: 10.1093/toxsci/kfl014
Accession: 011955678

Download citation:  
Text
  |  
BibTeX
  |  
RIS

Article/Abstract emailed within 0-6 h
Payments are secure & encrypted
Powered by Stripe
Powered by PayPal

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 (PPAR alpha). Due to its fatty acid structure, PFOA may activate other NRs, such as PPAR beta, PPAR gamma, liver X receptor (LXR), or retinoid X receptor (RXR). In this study, the activation of human, mouse, and rat PPAR alpha, PPAR beta, PPAR gamma, LXR beta, and RXR alpha 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 alpha were activated by PFOA isomers and PFOS. PPAR beta was less sensitive to the agents tested, with only PFOA affecting the mouse receptor. PFOA and PFOS also activated human, mouse, and rat PPAR gamma, although the maximum induction of PPAR gamma was much less than that seen with rosiglitazone, suggesting that PFOA and PFOS are partial agonists of this receptor. Neither LXR beta nor the common heterodimerization partner RXR alpha was activated by PFOA in any species examined. Taken together, these data show that of the NRs studied, PPAR alpha is the most likely target of PFOA and PFOS, although PPAR gamma 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.