Adolescent bone health under threat: PFAS mixtures as drivers of skeletal fragility

• Single PFAS showed negatively associations with BMD, differing by PFAS type and bone site. • Co-exposure to six PFASs significantly reduced BMD across various bone sites. • Me-PFOSA-AcOH was the dominant contributor to the combined effect of PFAS on BMD in adolescents. • In the combined effect, PFDeA was identified as the most significant PFAS in girls. Evidence regarding the effect of per- and poly-fluoroalkyl substances (PFASs) on bone minerals density (BMD) at various bone sites and the combined effects of PFAS mixtures is limited, particularly during the critical period of skeletal development. To address this gap, we conducted a cross-sectional study involving 1212 adolescents aged 12−19 years in NHANES 2011−2018 to examine the associations of single PFAS and PFAS mixtures with BMD at 11 bone sites and two comprehensive BMD indices. Multiple linear regression showed that serum PFAS concentrations were inversely associated with BMD, with variations according to the specific PFAS and bone site, and exhibiting a sex-specific pattern. Additionally, these associations differed significantly between obese and non-obese individuals, which was confined to boys. Mixture analysis using weighted quantile sum regression and Bayesian kernel machine regression revealed inverse associations between PFAS mixtures and BMD at specific bone sites, and 2-(N-methylperfluoroctanesulfonamido)acetic acid (Me-PFOSA-AcOH) and perfluorodecanoic acid (PFDeA) were identified as the dominant contributors to the combined effect of PFAS mixtures on BMD among all participants and girls, respectively. These findings lay a critical foundation for future environmental epidemiology studies and necessitate further exploration and validation of mechanisms through laboratory research.