Activation of mouse and human peroxisome proliferator-activated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths

Perfluoroalkyl acids (PFAAs) are surfactants used in consumer products and persist in the environment. Some PFAAs elicit adverse effects on rodent development and survival. PFAAs can activate peroxisome proliferator-activated receptor alpha (PPAR alpha) and may act via PPAR alpha to produce some of their effects. This study evaluated the ability of numerous PFAAs to induce mouse and human PPAR alpha activity in a transiently transfected COS-1 cell assay. COS-1 cells were transfected with either a mouse or human PPAR alpha receptor-luciferase reporter plasmid. After 24 h, cells were exposed to either negative controls (water or dimethyl sulfoxide, 0.1%); positive control (WY-14643, PPAR alpha agonist); perfluorooctanoic acid or perfluorononanoic acid at 0.5-100 mu M; perfluorobutanoic acid, perfluorohexanoic acid, perfluorohexane sulfonate, or perfluorodecanoic acid (PFDA) at 5-100 mu M; or perfluorobutane sulfonate or perfluorooctane sulfonate at 1-250 mu M. After 24 h of exposure, luciferase activity from the plasmid was measured. Each PFAA activated both mouse and human PPAR alpha in a concentration-dependent fashion, except PFDA with human PPAR alpha. Activation of PPAR alpha by PFAA carboxylates was positively correlated with carbon chain length, up to C9. PPAR alpha activity was higher in response to carboxylates compared to sulfonates. Activation of mouse PPAR alpha was generally higher compared to that of human PPAR alpha. We conclude that, in general, (1) PFAAs of increasing carbon backbone chain lengths induce increasing activity of the mouse and human PPAR alpha with a few exceptions, (2) PFAA carboxylates are stronger activators of mouse and human PPAR alpha than PFAA sulfonates, and (3) in most cases, the mouse PPAR alpha appears to be more sensitive to PFAAs than the human PPAR alpha in this model.