A Genomic Framework for Evaluating the Impact of Per- and Polyfluoroalkyl Substances on Bone Health

Background: Per- and polyfluoroalkyl substances (PFASs), particularly PFOA and PFOS, are widespread environmental pollutants known for their biological persistence and systemic toxicity. While mounting evidence implicates PFASs in bone metabolism disturbances, their precise role in skeletal physiology and pathology remains unclear. Objective: To comprehensively evaluate the potential biological effects of PFOA and PFOS exposure on a wide spectrum of bone-related traits, spanning molecular, hormonal, and clinical endpoints. Methods: This study integrates large-scale genomic data from European-ancestry populations to investigate causal relationships between genetically predicted PFAS exposure and bone health using a bidirectional two-sample Mendelian Randomization framework. We employed a two-stage approach: first examining physiological indicators (bone mineral density, turnover markers, mineral metabolism, regulatory hormones), then assessing clinical skeletal disorders (osteoporosis, fractures, neoplasms, osteoarthritis). Genetic instruments were rigorously selected and validated to minimize confounding. Multiple complementary MR methods (inverse-variance weighted primary; sensitivity analyses including MR-Egger and weighted median) were applied alongside extensive validation for instrument validity and robustness. Furthermore, mediation analyses investigated biological pathways underlying observed associations. Results: Genomic evidence revealed significant associations between genetically predicted PFAS exposure and alterations in key bone physiological traits. Specifically, elevated PFOA levels were linked to increased parathyroid hormone-related protein and collagen alpha-1(XX) chain, while PFOS was associated with changes in circulating parathyroid hormone and reduced calcaneal bone density. Notably, PFOA exposure showed strong causal relationships with multiple skeletal pathologies, including benign bone tumors, osteonecrosis, and spine fractures. These findings were robust across multiple sensitivity analyses, and reverse-direction MR testing excluded reverse causality from bone traits to PFAS levels. Conclusion: This study provides a panoramic genetic overview of how environmental PFAS exposure may influence bone integrity through hormonal dysregulation and matrix remodeling. These results not only deepen the mechanistic understanding of PFAS toxicity in skeletal systems but also highlight actionable targets for environmental health interventions and public policy.