Effects of legacy and emerging per- and polyfluoroalkyl substances on PPARα/β/γ regulation and osteogenic/adipogenic differentiation. (December 2022)

• Record Type: Journal Article
• Authors: Qin, Hui; Niu, Yuxin; Luan, Haiyang; Li, Minghan; Zheng, Lu; Pan, Yifan; Liu, Wei
• Is Part Of: Environment international. Volume 170(2023)
• Publication Date: 2022-12
• Subjects: Perfluorinated substances -- PPARs -- Human mesenchymal stem cells -- Multipotent differentiation -- Molecular initiating event; Environmental protection -- Periodicals; Environmental health -- Periodicals; Environmental monitoring -- Periodicals; Environmental Monitoring -- Periodicals; Environnement -- Protection -- Périodiques; Hygiène du milieu -- Périodiques; Environnement -- Surveillance -- Périodiques; Environmental health; Environmental monitoring; Environmental protection; Periodicals; 333.705
• DOI: 10.1016/j.envint.2022.107584
• Languages: English
• ISSNs: 0160-4120

Abstract

Graphical abstract: Highlights: PFASs increased PPARα/β/γ expression in proliferating and differentiating cells. HFPO-DA and HFPO-TA altered osteogenesis and adipogenesis with similar potency to PFOA. PFOS and PFHxS reduced osteogenesis, but 6:2Cl-PFESA enhanced osteogenesis. PFASs decreased OPG/RANKL ratio in favor of osteoclastogenesis. PPARβ expression is positively correlated with osteogenesis affected by 6:2Cl-PFESA. Abstract: As the primary molecular target, there is still a gap between the peroxisome proliferator-activated receptors (PPARs) regulation and the adverse health effects caused by per- and polyfluoroalkyl substances (PFASs). The effects of PFASs on cellular differentiation regulated by PPARs is likely significant given the association of PFASs exposure with obesity and decreased bone density. Human mesenchymal stem cells (hMSCs) were used as an in vitro model to assess the roles of PPAR subtypes in the multipotent differentiation of hMSCs affected by perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA) and their replacement compounds. PFASs increased the expression of three PPAR subtypes in proliferating and differentiating hMSCs. Meanwhile, PFOS and PFOA decreased osteogenesis, enhanced adipogenesis, and increased bone turnover in hMSCs. Similarly, PFOA alternatives, hexafluoropropylene oxide dimer acid (HFPO-DA) and hexafluoropropylene oxide trimer acid (HFPO-TA), exhibited similar or even higher potency in affecting stem cell differentiation compared with PFOA. Perfluorohexanesulfonate (PFHxS) inhibited osteogenesis with comparable potency to PFOS. In contrast, 6:2 chlorinated poly-fluoroalkyl ether sulfonate (6:2Cl-PFESA) enhanced osteogenesis. PPARβ expression is significantly positively correlated with osteogenesis and osteoprotegerin (OPG) secretion in 6:2Cl-PFESA treated cells. shRNA knockdown of PPARβ remarkably reversed the osteogenic effects of 6:2Cl-PFESA and enhanced the adipogenic effects of the six chemicals. The results suggested that the adverse effects and relative potency of PFASs on the multipotent differentiation of hMSCs were dependent on the integrated action of the three PPAR subtypes, which facilitates a better understanding of the molecular initiating events of PFASs. The present study may well explain the mechanism of the decreased bone density and increased obesity incidence among those exposed to legacy PFASs, and indicates the necessity of further health risk assessment for the alternatives.