The molecular mechanism of the antagonistic activity of hydroxylated polybrominated biphenyl (OH-BB80) toward thyroid receptor β

Polybrominated biphenyls (PBBs) were widely used as additive brominated flame retardants. Their hydroxylated products (OH-PBBs) have been detected frequently in various marine mammals, causing an increased health risk. Till now, there lacks information on the potential disruption of OH-PBBs toward thyroid hormone receptor (TR) and the molecular characteristics of their interactions remain largely unknown. We herein in vitro and in silico evaluated the disrupting effect of 3,3',5,5'-tetrabromobiphenyl (BB80) and its metabolite 2,2'-dihydroxy- 3,3',5,5'-tetrabromobiphenyl (OH-BB80) toward human TR. The recombinant human TRβ two-hybrid yeast assay reveals the moderate antagonistic activity of OH-BB80 with IC₂₀ at 2 μmol/L, while BB80 shows no agonistic or antagonistic activity. OH-BB80 binds at the binding cavity of TRβ ligand binding domain (LBD) and forms one hydrogen bond with Phe272. Electrostatic interactions and hydrophobic interactions contribute much to their interactions. The binding of OH-BB80 quenches the intrinsic fluorescence of TRβ LBD at static quenching mode. Our study extends knowledge on the endocrine disrupting effect of OH-PBBs and suggests the full consideration of the biotransformation for further health risk assessment of PBBs and related structurally similar emerging contaminants.