Bisphenol A Analogs Induce Cellular Dysfunction in Human Trophoblast Cells in a Thyroid Hormone Receptor-Dependent Manner: In Silico and In Vitro Analyses

Bisphenol A (BPA) and its analogs are frequently detected in human daily necessities and environmental media. Placental thyroid hormone plays an important role in fetal development. Herein, we followed the adverse outcome pathway (AOP) to explore the toxic mechanisms of BPA and its analogs toward placental thyroid hormone receptor (TR). First, the TOX21 database was used, and the interactions between BPA analogs and the ligand-binding domains (LBDs) of two subtypes of TR (TRα and TRβ) were subjected to in silico screening using molecular docking (MD) and molecular dynamics simulation (MDS). Fluorescence spectra and circular dichroism (CD) showed that BPA and its analogs interfere with TRs as a molecular initiation event (MIE), including static fluorescence quenching and secondary structural content changes in TR-LBDs. Key events (KEs) of the AOP, including the toxicity induced in placental chorionic trophoblast cells (HTR-8/SVneo) by an inverted U-shaped dose effect and changes in ROS levels, were tested in vitro. BPA, BPB, and BPAF significantly changed the expression level of TRβ, and only BPAF significantly downregulated the expression level of TRα. In conclusion, our study contributes to the health risk assessment of BPA and its analogs regarding placental adverse outcomes (AOs).