Metabolic perturbations associated with per- and polyfluoroalkyl substances and their relationships with glycated hemoglobin in the Dutch PIAMA birth cohort

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have gained significant attention due to their ubiquity, persistence, and associations with an increased risk of several human diseases. However, the metabolic perturbations linking PFAS exposure and metabolic disorders, including type 2 diabetes (T2D), are unclear. METHODS: We assessed exposure to 11 PFAS and performed untargeted metabolomic profiling using 669 blood samples from 520 children in the Dutch PIAMA cohort, collected at ages 8, 12, and 16 years. Glycated hemoglobin (HbA1c), an indicator of long-term blood glucose levels and an established marker for assessing T2D risk, was measured in a subset of 441 children who contributed 538 samples, with no HbA1c data available at age 8. We applied weighted linear mixed models to conduct three cross-sectional metabolome-wide association studies (MWASs). First, a two-step approach was performed to identify PFAS-associated annotated metabolites (step 1, MWAS-1) and examine their associations with HbA1c (step 2). Then, we investigated metabolic pathways perturbed by PFAS exposures (MWAS-2) or associated with HbA1c (MWAS-3). RESULTS: In total, 37,268 features were assessed, of which 591 were level 1 annotated metabolites. Between 0 and 316 metabolites (out of 591) were associated with individual PFAS. Among these, five-oleoyl-glycerol, sphinganine, taurine, N-acetylglycine, and oxoglutarate-showed overlapping (mostly positive) associations with HbA1c and at least one PFAS (predominantly long-chain). At the pathway level, several PFAS were strongly linked to the enriched lipid and amino acid metabolism pathways, whereas no pathway was associated with HbA1c. CONCLUSION: This study highlights the interplay between certain PFAS, metabolic perturbations, and glycemic control. Additional research is needed to validate our results and explore PFAS effects on T2D.