Endocrine disruption: Molecular interactions of environmental bisphenol contaminants with thyroid hormone receptor and thyroxine-binding globulin

Many bisphenol A (BPA) analogs have been commercially used recently, such as 2,2-bis(4-hydroxyphenyl)butane (BPB), 4,4 '-ethylidenebisphenol, 4,4 '-methylenediphenol (BPF), 4,4 '-(1,4-phenylenediisopropylidene)bisphenol (BPP), 4,4 '-dihydroxydiphenyl sulfone (BPS), 4,4 '-cyclohexylidenebisphenol (BPZ), 4,4 '-(hexafluoroisopropylidene)diphenol (BPAF), 4,4 '-(1-phenylethylidene)bisphenol (BPAP), and 2,2-bis(4-hydroxy-3,5-dimethylphenyl)propane (TMBPA), to circumvent adverse effects of BPA. However, their increasing use is also contaminating the environment, which is a potential cause of concern for human health. Thyroid hormone transport and signaling are potential targets for endocrine-disrupting activity of BPA analogs. Thyroxine-binding globulin (TBG) is the major carrier protein for thyroxine (T4) and triiodothyronine (T3) in blood. Thyroid hormones exert their action through thyroid hormone receptors (TR alpha and TR beta). This report presents the thyroid-disrupting potential of indicated nine BPA analogs from structure-based studies with TBG and TR alpha. Each BPA analog formed important polar and hydrophobic interactions with a number of residues of TBG and TR alpha. Majority of TBG residues (77-100%) and TR alpha residues (70-91%) interacting with BPA analogs were common with those of native ligands T4 and T3, respectively. Majority of BPA analogs interacted with TBG forming a salt bridge interaction at Lys-270. The hydrogen-bonding interaction of T3 with TR alpha at His-381 was also shared by majority of analogs. The binding energy for BPP, BPB, BPZ, BPAP, and TMBPA with both proteins was closer to binding energy of respective native ligands. The similarity in structural binding characteristics suggested potential disrupting activity of thyroid hormone signaling and transport.