Relationship between peroxisome proliferator‐activated receptor alpha activity and cellular concentration of 14 perfluoroalkyl substances in HepG2 cells

Abstract

Peroxisome proliferator-activated receptor alpha (PPARα) is a molecular target for perfluoroalkyl substances (PFASs). Little is known about the cellular uptake of PFASs and how it affects the PPARα activity. We investigated the relationship between PPARα activity and cellular concentration in HepG2 cells of 14 PFASs, including perfluoroalkyl carboxylates (PFCAs), perfluoroalkyl sulfonates and perfluorooctane sulfonamide (FOSA). Cellular concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry and PPARα activity was determined in transiently transfected cells by reporter gene assay. Cellular uptake of the PFASs was low (0.04-4.1%) with absolute cellular concentrations in the range 4-2500 ng mg protein. Cellular concentration of PFCAs increased with perfluorocarbon chain length up to perfluorododecanoate. PPARα activity of PFCAs increased with chain length up to perfluorooctanoate. The maximum induction of PPARα activity was similar for short-chain (perfluorobutanoate and perfluoropentanoate) and long-chain PFCAs (perfluorododecanoate and perfluorotetradecanoate) (approximately twofold). However, PPARα activities were induced at lower cellular concentrations for the short-chain homologs compared to the long-chain homologs. Perfluorohexanoate, perfluoroheptanoate, perfluorooctanoate, perfluorononanoate (PFNA) and perfluorodecanoate induced PPARα activities >2.5-fold compared to controls. The concentration-response relationships were positive for all the tested compounds, except perfluorooctane sulfonate PFOS and FOSA, and were compound-specific, as demonstrated by differences in the estimated slopes. The relationships were steeper for PFCAs with chain lengths up to and including PFNA than for the other studied PFASs. To our knowledge, this is the first report establishing relationships between PPARα activity and cellular concentration of a broad range of PFASs.

Perfluorooctanoic acid activates multiple nuclear receptor pathways and skews expression of genes regulating cholesterol homeostasis in liver of humanized PPARα mice fed an American diet

“…Studies using reporter assays show that hPPARα is activated by PFAS. hPPARα activation increases with perfluoroalkyl acid chain length up to 8 carbons, yet all carbon chain lengths tested (i.e., C4 to C12) significantly activate PPARα (Behr et al 2019;Maloney and Waxman 1999;Rosenmai et al 2018;Takacs and Abbott 2007;Vanden Heuvel et al 2006). hPPARα target gene expression is induced by PFAS in human hepatocyte models, including primary hepatocytes (Behr et al 2019;Bjork et al 2011;Buhrke et al 2013;Buhrke et al 2015;Peng et al 2013;Rosen et al 2013;Wolf et al 2012;Wolf et al 2008).…”

Application of the Key Characteristics of Carcinogens to Per and Polyfluoroalkyl Substances

“…PFOA interacts with the ligand binding domain of estrogen receptors and while GenX had weaker estrogen binding ability, similar hexafluoropropylene homologues exhibited stronger affinity [178]. PFAS of varying chain lengths and structure, from C4 to C12 carboxylates and C4, C6 and C8 sulfonates were shown to intracellularly activate human and mouse PPARα [179,180]. Other studies indicate that PFOA may exert anti-androgenic effects through reduced testosterone binding to androgen receptor [158].…”

“…Animal Biosassay In Vitro PFOA Association: [153]; [154]; [155]; [156]; [157] Association: reviewed in [164]; [91]; [165]; [166]; [169]; [170]; [173]; [175]; [191]; [61] No association: [174] Association: [176]; [158]; [175]; [181]; [188]; [189]; [193]; [179]; [180] No association: [182] Long-chain PFAS a PFOS Association: [154]; [155]; [156]; [157]; [160]; reviwed in [163] No Association: [153] Association: [191]; [192] Association: [177]; [175]; [181]; [188]; [189]; [193]; [179]; [180] No association: [182] PFHxS Association: [159]; reviwed in [163] No association: [...…”

“…Association: [156]; [160] Association: [188]; [189]; [180] No association: [179] PFDoA Association: [188]; [189]; [179] No association: [180]…”

“…PFTrDA Association: [189] PFTeDA Association: [188]; [189]; [179] 8:2 FTOH Association: [184]; [185] No association: [188] 8:2 monoPAP Association: [184]; [185] 8:2 diPAP Association: [184] 8:2 triPAP Association: [184] 10:2 diPAP Association: [184] Short-chain PFAS b PFBS Association: [190] Association: [175]; [188]; [189]; [179]; [180] No association: [182] PFHxA…”