Association of per- and polyfluoroalkyl substances exposure and type 2 diabetes risk with the mediating role of platelet mitochondrial DNA methylation in the elderly.

The association between per- and polyfluoroalkyl substances (PFASs) exposure and incident type 2 diabetes mellitus (T2DM) and the underlying mechanisms in the elderly remain elusive. This prospective nested case-control study included 119 T2DM cases and 238 matched controls, aiming to explore the associations between PFASs exposure and T2DM risk and assess the mediating effect of platelet mitochondrial DNA (mtDNA) methylation on the PFASs-T2DM association. We measured plasma concentrations of 19 PFASs and assessed platelet mtDNA methylation at 10 specific CpG sites of genes. Logistic regression identified PFDA, PFUnDA, and PFHpS as positively associated with T2DM risk (P < 0.05 and PFDR <0.2). Mixture analyses using WQS, qgcomp, and BKMR models showed no statistically significant overall association between combined PFASs exposure and T2DM. Platelet mtDNA methylation was significantly correlated with PFASs exposure and T2DM. Notably, methylation at MT-ATP6-Pos2 statistically accounted for 73.7% of the association between PFUnDA and T2DM in the mediation model. Our findings suggest that specific PFASs may elevate T2DM risk in the elderly, partly through epigenetic alterations in platelet mtDNA, highlighting mtDNA methylation as a potential mechanistic link in environmental and diabetes.