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Activation of Mouse and Human Peroxisome Proliferator-Activated Receptors (Ppar Alpha, Gamma, Beta Delta) by Perfluorooctanoic Acid (Pfoa) and Perfluorooctane Sulfonate (PFOS)
Citation:
TAKACS, M. L. AND B. D. ABBOTT. Activation of Mouse and Human Peroxisome Proliferator-Activated Receptors (Ppar Alpha, Gamma, Beta Delta) by Perfluorooctanoic Acid (Pfoa) and Perfluorooctane Sulfonate (PFOS). TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 95(1):108-117, (2007).
Impact/Purpose:
This paper represents the continuing efforts at ORD, in response to the call for assistance from OPPTS, to investigate the potential ecological and human risk assessment for perfluoroalkyl acids (PFAA). Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are compounds which are persistent and is found ubiquitously in the environment, wildlife and humans. Previous cell based in vitro studies have shown that PFOA and PFOS are able to significantly activate peroxisome proliferator-activated receptors (PPARs). This study evaluates the potential for PFOA and PFOS to activate specific mouse and human PPAR α, β/δ, γ isoforms and to determine the effect of specific PPAR antagonists on that activation. This study demonstrated that PFOA is more potent than PFOS in activating PPARα and that the mouse PPARα is more responsive than human, PFOA and PFOS activated mouse, but not human, PPARβ/δ, and neither PFOA nor PFOS activated mouse or human PPARγ reporters
Description:
This study evaluates the potential for perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) to activate peroxisome proliferator-activated receptors (PPARs), using a transient transfection cell assay. Cos-1 cells were cultured in DMEM with fetal bovine serum (FBS) in 96-well plates and transfected with mouse or human PPAR alpha ({alpha}), beta ({beta}/{delta}), or gamma ({gamma}) reporter plasmids. Transfected cells were exposed to PFOA (0.5-100 µM), PFOS (1-250 µM), positive controls (i.e. known agonists and antagonists), and negative controls (i.e. DMEM, 0.1% water, and 0.1% DMSO). Following treatment for 24 hours, activity was measured using the Luciferase reporter assay. In this assay, PFOA had more transactivity than PFOS with both the mouse and human PPAR isoforms. PFOA significantly increased mouse and human PPAR{alpha} and mouse PPAR{beta}/{delta} activity relative to vehicle. PFOS significantly increased activation of mouse PPAR{alpha} and PPAR{beta}/{delta} isoforms. No significant activation of mouse or human PPAR{gamma} was observed with PFOA or PFOS. The PPAR{alpha} antagonist, MK-886, significantly suppressed PFOA and PFOS activity of mouse and human PPAR{alpha}. The PPAR{gamma} antagonist, GW9662, significantly suppressed PFOA activity on the human isoform. In conclusion, this study characterized the dose response and differential activation of mouse and human PPAR {alpha}, {beta}/{delta}, {gamma} by PFOA and PFOS. While this model allows opportunities to compare potential activation by perfluoroalkyl acids (PFAAs), it only evaluates the interaction and activation of the PPAR reporter constructs and is not necessarily predictive of a toxicological response in vivo.
