Per-and polyfluoroalkyl substances, seminal plasma metabolome, and sperm telomere length and mitochondrial DNA copy number: a cohort study

This study investigated the associations between exposure to 16 per- and polyfluoroalkyl substances (PFAS), seminal plasma metabolome, and sperm telomere length (STL) and mitochondrial DNA copy number (mtDNAcn) among more than 1000 healthy Chinese men screened as potential sperm donors. No associations were observed between PFAS concentrations in blood or seminal plasma and sperm mtDNAcn. However, PFAS concentrations in seminal plasma, but not blood plasma, were associated with longer STL in both single-chemical and mixture models (all FDR-adjusted P < 0.05). Metabolome-wide association analyses identified 79 metabolites associated with seminal PFAS concentrations and 62 metabolites associated with STL. Among these, 18 overlapping metabolites were enriched in pathways related to steroid metabolism and unsaturated fatty acid metabolism, suggesting potential metabolic processes linking seminal PFAS exposure with STL. Exploratory indirect-effect analyses further identified 12 metabolites with indirect-effect proportions ranging from 5.6% to 15.2%. Our findings provide novel insights into potential metabolic pathways linking PFAS exposure with sperm telomere biology and highlight the utility of untargeted metabolomics for generating hypotheses about potential biological mechanisms.