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 (n = 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.