Binding activities of bisphenol analogues toward TTR and TBG and their potential to disrupt thyroid hormone homeostasis

Bisphenol analogues (BPs) are widely used industrial chemicals, raising concern regarding their potential disruption of the thyroid hormone (TH) system. This study systematically evaluated the binding properties and interference potential of 21 structurally diverse BPs toward transthyretin (TTR) and thyroxine-binding globulin (TBG). Fluorescence polarization assays showed that TTR binding was primarily driven by bridging-group rigidity, halogen substitution, and hydroxyl number, whereas TBG affinity was more dependent on molecular polarity and steric volume. Molecular docking supported the roles of halogenation and structural complementarity in stabilizing ligand-protein interactions. A quantitative in vitro to in vivo extrapolation (QIVIVE) model predicted that environmentally relevant exposure levels of most BPs cause negligible alterations in serum free T4, and mixture effects were approximately additive. Toxicological Priority Index (ToxPi) integration identified highly halogenated congeners as dominant high-risk candidates, with substantially greater potential impacts under occupational high-exposure scenarios. Overall, this work establishes a multi-tiered framework linking molecular binding characteristics to in vivo hormone perturbations, providing scientific support for evaluating TH-disrupting risks and guiding the identification of safer BP alternatives.