Sex-specific associations between per- and polyfluoroalkyl substance exposure and epigenetic age: Findings from the National Health and Nutrition Examination survey 1999–2000

Per-and polyfluoroalkyl substances (PFAS) are a pervasive family of synthetic compounds with a wide range of reported health effects. Epigenetic clocks, DNA methylation-based predictors of chronological and biological age, are promising biomarkers for characterizing biological aging in humans. The potential impact of PFAS exposure on epigenetic aging in the general US population remains unclear. In the 1999–2000 National Health and Nutrition Examination Survey (NHANES) cycle (N = 262), eleven PFASs were measured in serum and DNA methylation was measured in blood with the EPICv1 array. Seven epigenetic clocks and their respective epigenetic age acceleration (EAA) measures were calculated. Survey-design weighted generalized linear regression models were used to test adjusted associations between individual log₂-transformed PFAS concentrations and EAA stratified by sex. Among male participants, doubling of PFNA concentrations was associated with greater EAA across several clocks including the Horvath clock (beta = 1.48, 95 % CI: 0.35, 2.61), Skin&Blood clock (beta = 1.27, 95 % CI: 0.21, 2.32), and PhenoAge (beta = 1.43, 95 % CI: 0.41, 2.44), and doubling of PFOS exposure was associated with greater Skin&Blood EAA (beta = 1.14, 95 % CI: 0.04, 2.24). When considering cell-adjusted EAA measures, each of these associations among male participants remained significant, and PFOSA was associated with decreased PhenoAge EAA (beta = −0.84, 95 % CI: −1.49, −0.18) and GrimAge2 EAA (beta = −0.81, 95 % CI: −1.51, −0.11) among female participants. In summary, we found evidence of sex-specific associations between PFAS exposure and epigenetic aging in a sample of older adults representative of the general US population.