Per- and polyfluorinated substances (PFAS) promote osteoclastogenesis and bone loss through PPARα activation

Per- and polyfluoroalkyl substances (PFAS) are emerging as significant environmental contaminants affecting bone health, with studies linking their exposure to decreased bone mineral density (BMD), enhanced osteoclastogenesis, and disruptions in the bone marrow microenvironment. While current research highlights the effects on bone and BMD, there is a critical gap in understanding the mechanisms behind these effects. Studies presented here investigate the effects of legacy and alternative PFAS, particularly hexafluoropropylene oxide dimer acid (GenX) and perfluorohexane sulfonic acid (PFHxS), on bone health using in vitro and in vivo models. An environmentally relevant mixture of five PFAS was found to promote osteoclastic differentiation of murine bone marrow macrophages (BMMs) in vitro. Among the five components of the Mixture, the emerging compound, GenX, had the highest propensity to induce osteoclastogenesis. Utilizing pharmacological and genetic approaches, we identified peroxisome proliferator-activated receptor alpha (PPARα) as a potential mediator of PFAS-driven osteoclastogenesis. Furthermore, our in vivo mouse experiments demonstrated a decrease in trabecular and cortical bone thickness as well as altered bone mineral composition in male FVB/N mice exposed to either GenX or PFHxS (2 mg/L) for 12 weeks. Altogether, our results reveal potentially negative effects of PFAS exposure on BMD, bone mineral composition, and overall bone health and underscore the need for further research assessing the health risks associated with exposure to alternative PFAS.