Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPAR alpha was activated by PFCs. However, the information on the binding interactions between PPAR gamma and PFCs and subsequent alteration of PPAR gamma activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPAR gamma ligand binding domain (hPPAR gamma-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group. For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted as hPPAR gamma agonists, and their potency correlated with their binding affinity with hPPAR gamma-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity. (C) 2014 Elsevier Inc. All rights reserved.