Associations between serum per- and polyfluoroalkyl substance concentrations and β-cell function and insulin resistance in adult females

CONTEXT: Epidemiological evidence of exposure to precursor and alternative per- and polyfluoroalkyl substances (PFASs) and metabolic health outcomes is lacking. OBJECTIVE: To quantify associations between concentrations of 31 PFAS and metabolic biomarkers of glucose homeostasis and β-cell function. METHODS: We used data from a 2018-2021 follow-up of the Maternal-Infant Research on Environmental Chemicals (MIREC) study, which included measurements of serum concentrations of PFAS and metabolic biomarkers in samples provided by 274 adult female participants. Our primary outcomes were composite measures of pancreatic β-cell function (proinsulin:insulin [PI:INS] and proinsulin:C-peptide [PI:CP] ratios) and insulin resistance (homeostatic model assessment for insulin resistance [HOMA-IR] and triglyceride-glucose [TyG] index). We used multivariable linear regression models to quantify the percent difference in outcome measures. Per- and polyfluoroalkyl substances with >50% detection (n = 17) were log2-transformed; PFAS with 10-50% detection (n = 14) were dichotomized at the limit of detection. We used quantile g-computation (qgcomp) and weighted quantile sum (WQS) regression to evaluate PFAS mixtures. We also modeled arithmetic sums of 17 PFAS detected in >50% of participants (Σ17PFAS) and 7 PFAS specified in the National Academies of Sciences, Engineering and Medicine report (Σ7PFAS). RESULTS: Each doubling of Σ7PFAS, PFOS, and PFHxS was associated with a 5-9% increase in PI:INS ratio. Σ7PFAS, but not the Σ17PFAS, was also positively associated with the PI:INS ratio in qgcomp models. We observed inverse associations between Σ7PFAS and HOMA-IR and fasting insulin. Many results were of small magnitude or imprecise. CONCLUSION: In this cross-sectional analysis, exposure to certain legacy, alternative, and precursor PFAS were associated with β-cell dysfunction.