A genomic framework for evaluating the impact of per- and polyfluoroalkyl substances on bone health

Per- and polyfluoroalkyl substances (PFASs), particularly perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), are persistent environmental pollutants increasingly implicated in bone metabolic disturbances, yet their roles in skeletal physiology and pathology remain insufficiently defined. To systematically evaluate the potential biological effects of PFOA and PFOS on a broad spectrum of bone-related physiological and clinical traits. Using large-scale genomic data from European-ancestry cohorts, we applied a two-sample Mendelian Randomization approach to assess the causal impact of genetically predicted PFAS exposure on bone phenotypes, complemented by sensitivity analyses and reverse-direction testing. Mediation analyses were performed to explore potential biological pathways. Genetically predicted PFAS exposure was associated with significant alterations in bone physiological markers. Higher PFOA levels were linked to increased parathyroid hormone–related protein and collagen alpha-1(XX) chain, whereas PFOS was associated with elevated parathyroid hormone and reduced calcaneal bone density. PFOA also demonstrated causal relationships with multiple skeletal pathologies, including osteonecrosis, benign bone tumors, and spine fractures. Results were consistent across sensitivity analyses, and reverse MR analyses did not support reverse causality. This study provides robust genetic evidence that PFAS exposure adversely affects bone metabolism and skeletal health. These findings underscore PFASs as potentially modifiable environmental risk factors for bone disorders and highlight mechanistic pathways that merit further experimental and cross-ancestry investigation.