Mechanistic Insights into Perfluoroalkyl Substance-Induced Thyroid Hormone Disruption during Pregnancy: Evidence from Metabolomic Mediation Analysis

Disruption of maternal thyroid homeostasis during pregnancy is of particular concern. Per- and polyfluoroalkyl substances (PFASs) can interfere with thyroid function, yet evidence in pregnant women and underlying mechanisms remain unclear. Here, we measured emerging and legacy PFASs, together with serum metabolomic profiles, in 540 pregnant women across two trimesters (<i>n</i> = 1180). Using a metabolome-wide association study combined with a meet-in-the-middle approach, we identified 92 key metabolites spanning 12 classes associated with both PFAS exposure and thyroid function. Pairwise mediation analysis revealed that several metabolites, notably cortisol, l-carnitine, and various amino acids, significantly mediated PFAS-thyroid associations. Pathway-level mediation further identified three principal mechanisms: interference with steroid hormone biosynthesis, mitochondrial dysfunction, and oxidative stress. Notably, we prompted a previously underappreciated mechanistic link whereby PFAS-induced alternations in cortisol may modulate the hypothalamic-pituitary-adrenal axis through negative feedback, thereby perturbing thyroid function. Emerging PFASs (PFO5DoDA, C9 HFPO-TA, and 6:2 Cl-PFESA) exhibited more extensive or similar metabolite-mediated effects on thyroid function compared with legacy PFOA and PFOS, suggesting that PFAS alternatives may pose greater risks for thyroid disruption. These findings show that prenatal PFAS exposure can disrupt maternal thyroid function through multiple metabolic pathways and highlight the necessity of PFAS exposure intervention in vulnerable populations.