Associations of Serum Per- and Polyfluoroalkyl Substances with Genotoxic Biomarkers: New Insights from Cross-Sectional and In Vivo Evidence
Peiwei Xu, Dihui Xu, Xiaofeng Wang, Zhijian Chen, Fengfeng Dong, Jie Xiang, Ping Cheng, Dandan Xu, Yuan Chen, Xiaoming Lou, Jiayin Dai, Yitao Pan
Abstract
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.