Per- and polyfluoroalkyl substance (PFASs) exposure is associated with metabolome perturbation and occurrence of gastric cancer

Background: Emerging evidence links per- and polyfluoroalkyl substances (PFASs) exposure to cancer, yet the specific connection to gastric cancer (GC) and underlying mechanisms remain underexplored. This study aims to analyze the role of metabolism in the association between PFASs and GC by integrating exposome and high-throughput metabolomics. Methods: In the study, we collected blood samples from 144 participants (50 GC cases and 94 controls). We detected ten targeted PFASs in plasma, including PFBS, PFDA, PFUnDA, PFHxA, PFOA, PFHpS, PFNA, PFOS, 6:2 Cl-PFESA and 8:2 Cl-PFESA. Metabolomics profiling was performed using ultra-performance liquid chromatography-mass spectrometry. Multivariable logistic regression assessed the correlations between PFASs and GC risk. Linear regression was applied to screen GC-associated metabolic biomarkers affected by PFASs. Pathway enrichment analysis was performed to illustrate the potential metabolic mechanisms of PFASs on the occurrence of GC. Findings: After adjusting for potential confounders (age, gender, smoking status, alcohol drinking and family history), we observed that PFBS (OR= 4.12, 95%CI: 1.70–9.96), PFDA, (OR=2.61, 95%CI: 1.08–6.30), and PFUnDA (OR=7.98, 95%CI: 3.04–20.92) were associated with increased GC risk. A notable disparity in metabolic profiling existed between GC and healthy controls. We identified 93 candidate differential blood metabolites between GC and control groups, and PFBS, PFDA, and PFUnDA exposure significantly altered 18, 5, and 45 GC-associated metabolic biomarkers, respectively. Those exposures upregulated pathways related to butanoate metabolism, valine, leucine, and isoleucine degradation, tyrosine metabolism, and fatty acid biosynthesis, while downregulated caffeine metabolism, D-amino acid metabolism, histidine metabolism, and glutathione metabolism. The stratified analysis revealed stronger associations in younger individuals, and similar findings were observed in males in the sensitivity analysis. Interpretation: This pioneering study provides essential evidence linking PFASs exposure, specifically PFBS, PFDA, and PFUnDA, to an increased risk of GC, illuminating the health implications of PFASs crisis to GC. Integrated analysis between exposome toxicology and metabolomics implied underlying mechanisms on alterations in key metabolic biomarkers and pathways. Funding: This study was supported by grants from the Healthy Zhejiang One Million People Cohort (K-20230085), the Medical and Health Research Project of Zhejiang Province (2024KY050), Zhejiang Cancer Hospital's National Natural Science Foundation Cultivation Fund (PY2022042) and Zhejiang Cancer Hospital Youth Research Fund (QN202201).