Multiple approaches to assess the effects of F-53B, a Chinese PFOS alternative, on thyroid endocrine disruption at environmentally relevant concentrations

A Chinese perfluorooctane sulfonate (PFOS) substitute frequently detected in the environment, 6:2 chlorinated polyfluorinated ether sulfonate (F-53B), has a similar structure to PFOS and it is proposed to cause thyroid dysfunction. To further confirm this hypothesis, the effects of F-53B on the thyroid endocrine system and underlying mechanisms were investigated in vitro and in vivo using rat pituitary GH3 cells and developing zebrafish, respectively. In GH3 cells, F-53B enhanced cell proliferation in a dose-dependent manner, indicative of thyroid receptor agonistic activity. In zebrafish larvae, F-53B exposure induced significant developmental inhibition and increased thyroxine (T 4 ) but not 3,5,3′-triiodothyronine (T 3 ) levels accompanied by a decrease in thyroglobulin (TG) protein and transcript levels of most genes involved in the hypothalamic-pituitary-thyroid (HPT) axis. Interestingly, T 4 levels remained significantly increased while TG protein and gene transcription levels were markedly upregulated after depuration. Molecular docking studies revealed that F-53B binds to transthyretin (TTR) by forming hydrogen bonds with Lys123 and Lys115, thereby interfering with thyroid hormone homeostasis. Our collective in vitro , in vivo and in silico studies provide novel evidence that F-53B disrupts the thyroid endocrine system at environmentally relevant concentrations, which cannot be recovered after depuration. Given the persistence of F-53B in the environment, the long-term consequences of thyroid hormone disruption by this chemical warrant further investigation.