Impacts of Gestational F-53B Exposure on Fetal Neurodevelopment: Insights from Placental and Thyroid Hormone Disruption

It has been evidenced that chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs) have strong potential cross the placental barrier, but their adverse effects on offspring remain unclear. In this study, pregnant mice received daily intraperitoneal injections of chlorinated polyfluorinated ether sulfonate (Cl-PFESA; commercially known as F-53B, primarily comprising 6:2 Cl-PFESA and 8:2 Cl-PFESA) at dosages of 40 and 200 μg/kg from gestational days 6 to 17. Following gestational exposure, distinct accumulation of 6:2 and 8:2 Cl-PFESAs was observed in both the placenta and fetal brain, confirming their penetration across the placental and fetal blood-brain barriers. Maternal exposure to F-53B disrupted the placental 11β-hydroxysteroid dehydrogenase type 2 (<i>hsd11b2</i>) barrier, characterized by hypermethylation of its promoter, decreased blood sinusoids in labyrinth layer, and downregulation of the nutrient transport genes, thereby severely impairing the placenta's protective and nutrient transfer functions. Concomitantly, significant fetal intrauterine growth restriction indicated by decreased fetal weight and crown-rump length was observed. Additionally, changes in thyroid hormones, along with transcriptional and DNA methylation alterations in the promoter regions of transthyretin (<i>ttr</i>) and deiodinase 3 (<i>dio</i>3) genes, were noted in the placenta. These epigenetic changes might affect the maternal-fetal transport of thyroid hormones, possibly leading to disrupted thyroid function in the F1 generation. With the decreased nutrient transport capacity of the placenta, T4 levels in the fetus are significantly reduced, resulting in significant fetal neurodevelopmental abnormalities, reduced nerve cell proliferation (Ki67), and damage to synaptic plasticity. This study reveals unveil the hidden dangers of F-53B, highlighting its neurotoxic effects on fetal development through the disruption of thyroid hormone transport across the placenta.