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Research article - Peer-reviewed, 2018

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

Rosenmai, Anna Kjerstine; Ahrens, Lutz; le Godec, Theo; Lundqvist, Johan; Oskarsson, Agneta

Abstract

Peroxisome proliferator-activated receptor alpha (PPAR) is a molecular target for perfluoroalkyl substances (PFASs). Little is known about the cellular uptake of PFASs and how it affects the PPAR activity. We investigated the relationship between PPAR 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 PPAR 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 4-2500ng mg(-1) protein. Cellular concentration of PFCAs increased with perfluorocarbon chain length up to perfluorododecanoate. PPAR activity of PFCAs increased with chain length up to perfluorooctanoate. The maximum induction of PPAR activity was similar for short-chain (perfluorobutanoate and perfluoropentanoate) and long-chain PFCAs (perfluorododecanoate and perfluorotetradecanoate) (approximately twofold). However, PPAR 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 PPAR 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 PPAR activity and cellular concentration of a broad range of PFASs.The relationship between peroxisome proliferator-activated receptor alpha (PPAR) activity and cellular concentrations of perfluoroalkyl substances was investigated in HepG2 cells. PPAR activity was determined in transiently transfected cells by reporter gene assay and cellular concentrations by high-performance liquid chromatography-tandem mass spectrometry The cellular concentrations and PPAR activity of perfluoroalkyl substances was dependent on perfluorocarbon chain -length and functional group, and positive relationships between PPAR activity and cellular concentrations were established for all compounds, except perfluorooctane sulfonate and perfluorooctane sulfonamide

Keywords

cellular concentration; perfluoroalkane sulfonamide; perfluoroalkyl carboxylates; perfluoroalkyl sulfonates; peroxisome proliferator-activated receptor alpha; PPAR

Published in

Journal of Applied Toxicology
2018, Volume: 38, number: 2, pages: 219-226