Differential Activation of Peroxisome Proliferator-Activated Receptor Alpha by Per- and Polyfluoroalkyl Substances

Per- and polyfluoroalkylated substances (PFAS) are persistent anthropogenic chemicals widely distributed in the environment that are known to have toxic effects in animals and humans following exposure. Some PFAS have been shown to activate peroxisome proliferator-activated receptor α (PPARα), a transcription factor involved in lipid metabolism, leading to dyslipidemia or liver toxicity. PFAS comprise a wide range of compounds, and variations in their structural characteristics could reveal important details regarding the level of PPARα activation. In this work, using a Chemically Activated LUciferase eXpression (CALUX) assay, we experimentally tested the PPARα activation efficiency of several PFAS compounds of varying chain lengths and functional groups. Activation and potency were compared across and within PFAS class based on chemical differences. When compounds with the same number of carbons or perfluorinated carbons were compared across class, the rank from high to low activator class remained the same. Perfluorocarboxylated ether was found to be the strongest class, while polyfluorotelomer was the weakest, suggesting the importance of structural features in PPARa activation. Perfluorocarboxylates were consistently better PPARα activators than perfluorosulfonates. Comparing within these 2 classes, the number of perfluorinated carbon atoms better predicted activation than the number of carbon atoms. In the perfluorocarboxylated ether, perfluorocarboxylate, and perfluorosulfonate classes, a direct correlation existed between potency and the percentage of PPARα activation (R² = 0.702), a novel observation. These findings provide new insights regarding distinct chemical characteristics of PFAS compounds which may be predictive of PPARα activation level.