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 tetrabromobisphenol A (TBBPA) are produced in large quantities for use in electronic equipment, plastics, and building ma terials. Because these compounds have some structural resemblance to the th yroid hormone thyroxine (T-4), it was suggested that they may interfere wit h thyroid hormone metabolism and transport, e.g., by competition with T-4 o n transthyretin (TTR). In the present study, we investigated the possible i nteraction of several brominated flame retardants with T-4 binding to TTR i n an in vitro competitive binding assay, using human TTR and I-125-T-4 as t he displaceable radioligand. Compounds were tested in at least eight differ ent concentrations ranging from 1.95 to 500 nM. In addition, we investigate d the structural requirements of these and related ligands for competitive binding to TTR. We were able to show very potent competition binding for TB BPA and PBP (10.6- and 7.1-fold stronger than the natural ligand T-4, respe ctively). PBDEs were able to compete with T-4-TTR binding only after metabo lic conversion by induced rat liver microsomes, suggesting an important rol e for hydroxylation. Brominated bisphenols with a high degree of brominatio n appeared to be more efficient competitors, whereas chlorinated bisphenols were less potent compared to their brominated analogues. These results ind icate that brominated flame retardants, especially the brominated phenols a nd tetrabromobisphenol A, are very potent competitors for T-4 binding to hu man transthyretin in vitro and may have effects on thyroid hormone homeosta sis in vivo comparable to the thyroid-disrupting effects of PCBs.