ToxSci Advance Access published online on August 18, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn166
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Published by Oxford University Press 2008
Activation of mouse and human peroxisome proliferator-activated receptor alpha (PPAR
) by perfluoroalkyl acids (PFAAs) of different functional groups and chain lengths
Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711
Address correspondence to: Cynthia J. Wolf, US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Reasearch Laboratory, Reproductive Toxicology Division, MD-67, Reasearch Triangle Park, NC 27711
Received May 22, 2008; revision received July 16, 2008; accepted August 6, 2008
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Abstract |
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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 PPAR
and may act via PPAR to produce some of their effects. This study evaluated the ability of numerous PFAAs to induce mouse and human PPAR activity in a transiently transfected COS-1 cell assay. COS-1 cells were transfected with either a mouse or human PPAR receptor-luciferase reporter plasmid. After 24 hours, cells were exposed to either negative controls (water or DMSO, 0.1%), positive control (WY-14,643, PPAR agonist); perfluorooctanoic acid (PFOA) or perfluorononanoic acid (PFNA) at 0.5-100 µM; perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorohexane sulfonate (PFHxS), or perfluorodecanoic acid (PFDA) at 5-100 µM; or perfluorobutane sulfonate (PFBS) or perfluorooctane sulfonate (PFOS) at 1-250 µM. After 24 hrs of exposure, luciferase activity from the plasmid was measured. Each PFAA activated both mouse and human PPAR in a concentration-dependent fashion, except PFDA with human PPAR. Activation of PPAR by PFAA carboxylates was positively correlated with carbon chain length, up to C9. PPAR activity was higher in response to carboxylates compared to sulfonates. Activation of mouse PPAR was generally higher compared to that of human PPAR. We conclude that, in general, (i) PFAAs of increasing carbon backbone chain lengths induce increasing activity of the mouse and human PPAR with a few exceptions, (ii) PFAA carboxylates are stronger activators of mouse and human PPAR than PFAA sulfonates, and (iii) in most cases, the mouse PPAR appears to be more sensitive to PFAAs than the human PPAR in this model.
Key Words: perfluoroalkyl acids; PFAA; peroxisome proliferator activated receptor-alpha; PPAR; PFOS; PFOA; PFNA; PFBA; transient transfection assay; COS-1 cells.
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