Prenatal per- and polyfluoroalkyl substances (PFAS) exposure and maternal thyroid homeostasis: Nonlinear, compound-specific, and mixture effects

Per - and polyfluoroalkyl substances (PFAS) are recognized thyroid disruptors, yet their impacts during early pregnancy—a critical window for fetal neurodevelopment—remain insufficiently characterized. In this study of 192 first-trimester pregnant women in Zhejiang, China, we measured eight PFAS and five thyroid hormones and applied advanced statistical models to evaluate individual and mixture effects. We identified novel L-shaped associations of perfluorooctane sulfonic acid and 6:2 chlorinated perfluoroether sulfonic acid with decreased total triiodothyronine (TT3) and thyroxine (TT4), suggesting potential threshold-dependent effects. Perfluorohexane sulfonic acid (PFHxS) exhibited a unique positive association with thyroid-stimulating hormone (TSH) and the TSH/free thyroxine (TSH/FT4) ratio, indicating activation of the hypothalamic-pituitary-thyroid axis feedback loop. Both PFHxS and perfluorodecanoic acid significantly altered TT3, TT3/free triiodothyronine (TT3/FT3) ratio, and TT4/FT4 ratio, implying interference with thyroid hormone transport and metabolism. Notably, perfluorotridecanoic acid emerged as the dominant contributor to disrupted FT3 levels and FT4/FT3 balance in Bayesian Kernel Machine Regression analysis, despite limited prior investigation. These findings highlight the compound specificity and synergistic effects of PFAS on maternal thyroid homeostasis, emphasize the necessity of multi-dimensional exposure assessment, and call for heightened regulatory attention, particularly toward long-chain PFAS substitutes. • L-shaped associations of PFOS and 6:2 Cl-PFESA with reduced TT3 and TT4 levels. • PFHxS uniquely associated with increased TSH and TSH/FT4 ratio among eight PFAS. • PFHxS and PFDA significantly altered TT3, TT3/FT3, and TT4/FT4 binding ratios. • PFTrDA showed a strong negative association with TT3 and dominated mixture effects. • BKMR modeling reveals PFAS mixtures impaired FT3 levels and FT4/FT3 balance.