Activation of Mouse and Human Peroxisome Proliferator–Activated Receptors (α, β/δ, γ) by Perfluorooctanoic Acid and Perfluorooctane Sulfonate

Abstract

This study evaluates the potential for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) to activate peroxisome proliferator-activated receptors (PPARs), using a transient transfection cell assay. Cos-1 cells were cultured in Dulbecco's Minimal Essential Medium (DMEM) with fetal bovine serum in 96-well plates and transfected with mouse or human PPARalpha, beta/delta, or gamma reporter plasmids. Transfected cells were exposed to PFOA (0.5-100 microM), PFOS (1-250 microM), positive controls (i.e., known agonists and antagonists), and negative controls (i.e., DMEM, 0.1% water, and 0.1% dimethyl sulfoxide). Following treatment for 24 h, 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 PPARalpha and mouse PPARbeta/delta activity relative to vehicle. PFOS significantly increased activation of mouse PPARalpha and PPARbeta/delta isoforms. No significant activation of mouse or human PPARgamma was observed with PFOA or PFOS. The PPARalpha antagonist, MK-886, significantly suppressed PFOA and PFOS activity of mouse and human PPARalpha. The PPARgamma 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 PPARalpha, beta/delta, gamma by PFOA and PFOS. While this model allows opportunities to compare potential activation by perfluoroalkyl acids, it only evaluates the interaction and activation of the PPAR reporter constructs and is not necessarily predictive of a toxicological response in vivo.

Tributyltin is a potent inhibitor of piscine peroxisome proliferator-activated receptor α and β

“…In previous studies on fish PPARs, PFOA has been shown to transactivate PPAR/RXR heterodimers (Leaver et al, 2005) and in mice and humans both PFOA and PFOA act as weak agonists in a similar Gal4-PPAR assay to that used here (Takacs and Abbott, 2007). However, plaice…”

Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARαand T- and B-cell targeting

“…PFOA has been reported to up-regulate human and mouse PPAR activity in vitro (Takacs and Abbott, 2007), while others have reported that PFOA does not activate humanized PPAR expressed in mice (Nakamura et al, 2009). The role of PPAR Figure 1.…”

Structure–activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor

“…Due to their structural similarity to fatty acids, previous mechanistic studies focused on PFCs' toxicity carried out through the peroxisome proliferator-activated receptor (PPAR) pathway (Wolf et al 2008). Direct binding and activation to PPARs have been demonstrated (Wolf et al 2012;Takacs and Abbott 2007). Recently, some other nuclear receptors, such as estrogen receptor (ER), constitutive androstane receptor, pregnane X receptor, androgen receptor, and aryl hydrocarbon receptor have also been identified as possible targets of PFCs (Benninghoff et al 2011;Bjork et al 2011;Gao et al 2013).…”