Potent Competitive Interactions of Some Brominated Flame Retardants and Related Compounds with Human Transthyretin in Vitro

Brominated flame retardants such as polybrominated diphenyl ethers (PBDEs), pentabromophenol (PBP), and tetrabromobisphe- nol A (TBBPA) are produced in large quantities for use in elec- tronic equipment, plastics, and building materials. Because these compounds have some structural resemblance to the thyroid hor- mone thyroxine (T4), it was suggested that they may interfere with thyroid hormone metabolism and transport, e.g., by competition with T4 on transthyretin (TTR). In the present study, we investi- gated the possible interaction of several brominated flame retar- dants with T4 binding to TTR in an in vitro competitive binding assay, using human TTR and 125 I-T4 as the displaceable radioli- gand. Compounds were tested in at least eight different concen- trations ranging from 1.95 to 500 nM. In addition, we investigated the structural requirements of these and related ligands for com- petitive binding to TTR. We were able to show very potent com- petition binding for TBBPA and PBP (10.6- and 7.1-fold stronger than the natural ligand T4, respectively). PBDEs were able to compete with T4-TTR binding only after metabolic conversion by induced rat liver microsomes, suggesting an important role for hydroxylation. Brominated bisphenols with a high degree of bro- mination appeared to be more efficient competitors, whereas chlo- rinated bisphenols were less potent compared to their brominated analogues. These results indicate that brominated flame retar- dants, especially the brominated phenols and tetrabromobisphenol A, are very potent competitors for T4 binding to human transthy- retin in vitro and may have effects on thyroid hormone homeosta- sis in vivo comparable to the thyroid-disrupting effects of PCBs.