Effects of early-life F-53B exposure on thyroid function in juvenile rats: The role of the cAMP signaling pathway

Chlorinated polyfluoroalkyl ether sulfonate (F-53B), a substitute for perfluorooctane sulfonate (PFOS), exerts a stronger effect on neonatal thyroid hormone (TH) than PFOS. However, limited data on its thyrotoxicity complicates early-life risk assessment. Here, Sprague-Dawley rats were gavaged with F-53B (0, 8, 80, 800 mu g/kg/d) for 63 days, from two weeks pre-pregnancy to two weeks post-weaning. The results showed F-53B accumulated in the juvenile rats thyroids, causing thyroid follicle colloid rupture and dysgenesis, marked by reduced thyroid transcription factor 1 and elevated paired box gene 8 expression. Furthermore, F-53B affects TH synthesis by decreasing the expression of thyroid peroxidase and thyroid-stimulating hormone receptor, and increasing type II deiodinase activity. In plasma, F-53B raised total thyroxine (TT4), suppressed free triiodothyronine and free thyroxine (FT4) levels, and lowered the FT4/TT4 ratio. Mechanistically, F-53B binds to the ligand-binding pockets of key downregulated genes (Calcitonin-related polypeptide alpha and Somatostatin) in the cyclic adenosine monophosphate (cAMP) pathway. This promoted the lower expressions of protein kinase A in the thyroid follicular cytoplasm and phosphorylated cAMP response element-binding protein (p-CREB1-S133) in the nucleus, potentially weakening TH synthesis genes transcription. Overall, this work provides pioneering insights into the thyrotoxicity mechanisms of F-53B, laying a foundation for endocrine risk assessment.