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).
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