Per- and polyfluoroalkyl substances (PFASs) exposure and gastric cancer risk: Insights from exposome-metabolome profiling

The environmental persistence and bioaccumulative nature of per- and polyfluoroalkyl substances (PFAS) have emerged as a critical environmental health concern, particularly regarding their carcinogenic potential. However, limited studies have systematically investigated the association between PFAS exposure and gastric cancer risk, particularly in high-incidence regions such as China. We quantified ten PFAS congeners and characterized metabolomic profiles in pre-treatment plasma samples from gastric cancer patients and matched controls using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multivariable logistic regression evaluated individual PFAS and GC risk. Mixture effects were interrogated via advanced multipollutant modeling techniques—Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation (qgcomp). Linear regression was applied to evaluate the association between PFAS levels and gastric cancer-associated metabolic biomarkers, and pathway enrichment analysis identified related metabolic pathways. Three legacy PFAS demonstrated independently positive relationships with gastric cancer risk: perfluorobutanesulfonic acid (PFBS) (adjusted OR=4.12, 95 %CI:1.70–9.96 per unit increase), perfluorodecanoic acid (PFDA) (OR=2.61, 95 %CI: 1.08–6.30), and perfluoroundecanoic acid (PFUnDA) (OR=7.98, 95 %CI: 3.04–20.92). These associations remained robust in high vs. low PFAS exposure comparisons. Multipollutant modeling showed no significant association between PFAS mixtures and gastric cancer risk. Metabolomic analysis revealed distinct perturbation patterns, with PFBS, PFDA, and PFUnDA correlated with 14, 6, and 62 gastric cancer-related metabolites, respectively. Enrichment analysis identified four significantly disrupted metabolic pathways: butanoate metabolism, D-amino acid metabolism, histidine metabolism, and glycerolipid metabolism. This study provides novel epidemiological evidence implicating specific PFAS congeners in gastric carcinogenesis, potentially mediated through metabolic pathway disruption. These results underscore the necessity for longitudinal studies to elucidate temporality and mechanistic underpinnings of PFAS-induced metabolic reprogramming in gastric cancer development. • Exposure to individual PFASs was associated with an increased risk for gastric cancer. • PFBS, PFDA and PFUnDA were significantly linked to an elevated risk for gastric cancer. • PFBS, PFDA and PFUnDA were significantly related to metabolic biomarkers of gastric cancer.