Associations of Serum Per- and Polyfluoroalkyl Substances with Genotoxic Biomarkers: New Insights from Cross-Sectional and In Vivo Evidence

The effects of perfluoroalkyl and polyfluoroalkyl substances (PFAS) on genomic stability remain unclear. Here, a cross-sectional study was conducted to establish the associations of PFAS with genotoxic biomarkers. We recruited a cohort of 453 residents in 2021 in Zhejiang, China. Thirty PFAS in serum were quantified, alongside seven indicators of genomic stability [five rDNA copy numbers (rDNA-CN), mitochondrial DNA copy numbers (mtDNA-CN), and relative telomere length (RTL)] in whole blood. Results showed that PFUnDA, perfluorohexanesulfonic acid (PFHxS), perfluorooctanesulfonic acid (PFOS), 6:2 Cl-PFESA, and PFO5DoDA were positively correlated with rDNA-CN, while PFHpA, PFOA, and PFMOAA showed inverse associations. PFO4DA and PFO5DoDA were positively correlated with mtDNA-CN. PFOA, HFPO-TA, and PFMOAA were negatively associated with the RTL, while perfluorononanoic acid, PFHxS, PFOS, and 6:2 Cl-PFESA showed positive associations. Nonlinear exposure-response relationships were also observed between PFAS and genotoxic biomarkers using restricted cubic spline models. Furthermore, PFAS mixtures were positively associated with mtDNA-CN, with PFO5DoDA showing the highest contribution by the quantile-based g-computation model. In vivo studies further confirmed that PFO5DoDA increased mtDNA-CN in male mice in a dose-dependent manner. This study provides novel evidence that PFAS disrupt genomic stability, with effects varying by functional groups and fluoroalkyl(ether) chain lengths.