Journal
TOXICOLOGY IN VITRO
Volume 62, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2019.104700
Keywords
PFAS; PFOA; PFOS; Nuclear receptor; PPAR alpha; Reporter gene assay
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [BU 3060/1-1]
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Perfluoralkylated substances (PFAS) such as perfluorooctanoic acid (PFOA) or perfluorooctanesulfonic acid (PFOS) are used to produce, e.g., surface coatings with water- and dirt-repellent properties. These substances have been shown to be hepatotoxic in rodents, and the mechanism of action is mostly attributed to the PFAS-mediated activation of the peroxisome proliferator-activated receptor alpha (PPAR alpha). In the present study, we investigated by using luciferase-based reporter gene assays whether PFOA, PFOS and six alternative PFAS can activate, in addition to PPAR alpha, eight other human nuclear receptors. All tested PFAS except for perfluorobutanesulfonic acid (PFBS) were able to activate human PPAR alpha. Perfluoro-2-methyl-3-oxahexanoic acid (PMOH) and 3H-perfluoro-3-[(3-methoxypropoxy) propanoic acid] (PMPP) were weak agonists of human PPAR gamma. The other human nuclear receptors (PPAR delta, CAR, PXR, FXR, LXR alpha, RXR alpha and RAR alpha) were not affected by any PFAS tested in this study. Although PMOH was more effective than PFOA in stimulating PPAR alpha in the transactivation assay, it was less effective in stimulating PPAR alpha-dependent target gene expression in human HepG2 hepatocarcinoma cells. Notably, any effect observed in this in vitro study only occurred at concentrations higher than 10 mu M of the respective PFAS which is in all cases several magnitudes above the average blood concentration in the Western population. Thus, the results suggest that nuclear receptor activation may only play a minor role in potential PFAS-mediated adverse effects in humans.
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