Metabolome-wide association study identifies metabolites associated with human exposure to perfluoroalkyl substances

BACKGROUND: Perfluoroalkyl substances (PFAS) are organic compounds with widespread environmental occurrence and documented associations with multiple health effects. The pathophysiology remains unclear, although there are indications of potential involvement of metabolic pathways. OBJECTIVE: To evaluate associations between serum PFAS concentrations and the metabolome in Swedish adults. METHODS: We conducted an extensive metabolome-wide association analysis (MWAS) to explore the potential links between serum metabolites and serum concentrations of PFOS, PFOA, and PFHxS in a cohort comprising 2353 participants from the EpiHealth study. Liquid chromatography coupled with mass spectrometry was used to obtain levels of PFAS and 790 distinct non-xenobiotic metabolites. Results were validated in 1104 participants from the POEM and PIVUS cohort. Linear regression models were adjusted for age, sex, BMI, smoking, exercise, education, and diabetes. RESULTS: 236 metabolites were validated to be significantly associated with PFOS, and 190 metabolites associated with PFOA using FDR < 0.05. No significant associations could be validated for PFHxS. The metabolites showing the strongest associations with both PFOS and PFOA were various lipid-related metabolites, including long-chain polyunsaturated fatty acids (n3 and n6), saturated fatty acids, and monounsaturated fatty acids. Also, lysophospholipids, sphingomyelins, phosphatidylcholines, as well as various amino acids, were related to the two PFAS. Metabolic pathway analysis identified significant enrichment of metabolites involved in branched-chain amino acid biosynthesis, synthesis of unsaturated fatty acids, and arginine biosynthesis. IMPACT STATEMENT: This study provides a large-scale, externally validated map of metabolites associated with background human exposure to major PFAS. In a population-based metabolome-wide association study (MWAS) with independent validation, PFOS and PFOA showed robust associations with lipid classes and amino acids, whereas no associations were validated for PFHxS. These findings strengthen biological plausibility for PFAS-health associations and prioritize metabolic pathways for future mechanistic and environmental epidemiology studies.