PFOS exposure and periodontitis from adolescent burden to genetic and multiomics evidence.

Periodontitis can develop early in life and may be influenced by persistent environmental exposures. We integrated Global Burden of Disease 2021 data, Mendelian randomization, transcriptomics, machine learning, immune profiling, single-cell analysis, molecular modeling, and in vitro validation to investigate links between perfluorooctane sulfonate exposure and periodontitis. Periodontal disease burden remained substantial among individuals aged 5-20 years and varied across sociodemographic strata. Genetically predicted PFOS exposure was associated with increased periodontitis risk by inverse-variance weighted Mendelian randomization. Multi-omics analyses identified 151 shared targets enriched in immune-inflammatory pathways and prioritized a ten-gene signature with strong diagnostic discrimination. Single-cell analysis implicated migration inhibitory factor (MIF)-centered immune communication, whereas molecular modeling supported stable PFOS-STK17B interactions. PFOS exposure in human gingival fibroblasts increased expression of the ten prioritized genes. These findings connect population burden with genetic, molecular, and experimental evidence supporting immune-inflammatory mechanisms linking PFOS exposure to periodontitis.