Chlorinated Polyfluorinated Ether Sulfonates Exhibit Higher Activity toward Peroxisome Proliferator-Activated Receptors Signaling Pathways than Perfluorooctanesulfonate

Abstract

Chlorinated polyfluorinated ether sulfonates (Cl-PFAESs) are the alternative products of perfluorooctanesulfonate (PFOS) in the metal plating industry in China. The similarity in chemical structures between Cl-PFAESs and PFOS makes it reasonable to assume they possess similar biological activities. In the present study, we investigated whether Cl-PFAESs could induce cellular effects through peroxisome proliferator-activated receptors (PPARs) signaling pathways like PFOS. By using fluorescence competitive binding assay, we found two dominant Cl-PFAESs (6:2 Cl-PFAES and 8:2 Cl-PFAES) bound to PPARs with affinity higher than PFOS. Based on the luciferase reporter gene transcription assay, the two Cl-PFAESs also showed agonistic activity toward PPARs signaling pathways with potency similar to (6:2 Cl-PFAES) or higher than (8:2 Cl-PFAES) PFOS. Molecular docking simulation showed the two Cl-PFAESs fitted into the ligand binding pockets of PPARs with very similar binding mode as PFOS. The cell function results showed Cl-PFAESs promoted the process of adipogenesis in 3T3-L1 cells with potency higher than PFOS. Taken together, we found for the first time that Cl-PFAESs have the ability to interfere with PPARs signaling pathways, and current exposure level of 6:2 Cl-PFAES in occupational workers has exceeded the margin of safety. Our study highlights the potential health risks of Cl-PFAESs as PFOS alternatives.

Interactions of Perfluorooctanesulfonate and 6:2 Chlorinated Polyfluorinated Ether Sulfonate with Human Serum Albumin: A Comparative Study

“…The protein binding properties of PFASs are key contributors to their bioaccumulation as well as to their biological effects on organisms. , A higher binding affinity to human liver fatty acid-binding protein for 6:2 Cl-PFESA compared to PFOS was reported in our previous study, which may lead to a more serious accumulation of 6:2 Cl-PFESA in the liver . Li et al reported tighter binding of 6:2 Cl-PFESA to peroxisome proliferator-activated receptors (PPARs) compared to that of PFOS, which was explained by the stronger activation of the PPAR pathways . Xin et al also observed a stronger binding potency for 6:2 Cl-PFESA than for PFOS to thyroid hormone transport proteins and a similar agonistic activity toward thyroid hormone receptors …”

“…23 Li et al reported tighter binding of 6:2 Cl-PFESA to peroxisome proliferator-activated receptors (PPARs) compared to that of PFOS, which was explained by the stronger activation of the PPAR pathways. 48 Xin et al also observed a stronger binding potency for 6:2 Cl-PFESA than for PFOS to thyroid hormone transport proteins and a similar agonistic activity toward thyroid hormone receptors. 49 The binding parameters of PFOS to HSA have been reported in several studies.…”

The Role of Persistent Organic Pollutants in Obesity: A Review of Laboratory and Epidemiological Studies

“…Specifically, perfluorobutanesulfonic acid (PFBS) used as a substituent for perfluorooctanesulfonic acid (PFOA) was demonstrated to be a proadipogenic agent, promoting the differentiation of 3T3-L1 preadipocytes to adipocytes by up-regulating PPARγ and C/EBPα transcription factors and lipogenic acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) [51]. In comparison to PFOS, chlorinated polyfluorinated ether sulfonates (Cl-PFAESs) were shown to be more potent stimulators of 3T3-L1 adipogenesis through the PPARγ pathway [52]. Perfluorinated alkyl acids (PFAAs) are also capable of inducing adipogenesis in 3T3-L1 cells at human blood-based exposure levels [53].…”

Applicability Domains Enhance Application of PPARγ Agonist Classifiers Trained by Drug-like Compounds to Environmental Chemicals

“…Peroxisome proliferator activator receptor gamma (PPARγ) is a member of nuclear receptor family that plays versatile roles in human physiology. , In the recent decade, transactivation of PPARγ has been found to be related to human fatty liver disease and endocrine-disrupting effects including undermined osteogenesis, promoted adipogenesis, and increased tendency toward later-life obesity. − PPARγ agonist activity of chemicals thus serves as an early indicator of the adverse health effects. Many chemicals such as organotins, phthalate esters, chlorinated polyfluorinated ether sulfonates, and brominated and organo-phosphorus flame retardants have been reported as PPARγ agonists in in vitro assays. − , However, in vitro assays are time-consuming and expensive, thus not suitable for screening of the huge amount of environmental chemicals.…”

“…Many chemicals such as organotins, phthalate esters, chlorinated polyfluorinated ether sulfonates, and brominated and organo-phosphorus flame retardants have been reported as PPARγ agonists in in vitro assays. [6][7][8][9][10][11][12][13]4 However, in vitro assays are time-consuming and expensive, thus not suitable for screening of the huge amount of environmental chemicals.…”