Structure-activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor

Area of Science:

• Environmental Toxicology
• Endocrinology
• Molecular Biology

Background:

• Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants suspected of endocrine disruption.
• Thyroid hormone receptors (TR) regulate crucial physiological processes.
• Direct binding of PFAS to TR has not been previously demonstrated.

Purpose of the Study:

• To investigate the direct binding interactions between various PFAS and human TR.
• To assess the functional activity of PFAS on TR in cellular and in vivo models.
• To elucidate the molecular mechanisms underlying PFAS-TR interactions.

Main Methods:

• Fluorescence competitive binding assays to determine PFAS binding affinity to TR.
• Cell proliferation assays to evaluate TR-mediated activity of PFAS.
• In vivo studies in amphibians to assess the effects of PFAS on thyroid hormone gene expression.
• Molecular docking to predict the binding mode of PFAS within the TR ligand-binding domain.

Main Results:

• Most tested PFAS bound to human TR, with binding potency influenced by chemical structure (e.g., chain length, functional group).
• Specific PFAS, including perfluorooctane sulfonate (PFOS), perfluorohexadecanoic acid, and perfluorooctadecanoic acid, exhibited agonistic activity on TR, promoting cell proliferation.
• PFOS exposure in vivo mimicked the effects of triiodothyronine (T3) on thyroid hormone-responsive gene expression in amphibians.
• Molecular docking revealed that PFAS fit into the T3-binding pocket of TR, forming similar interactions as T3.

Conclusions:

• The study provides strong evidence that certain PFAS directly bind to TR.
• These interactions can lead to the disruption of thyroid hormone signaling pathways.
• PFAS represent a potential threat to thyroid homeostasis through direct TR modulation.