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