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

Abstract

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 materials. Because these compounds have some structural resemblance to the thyroid hormone thyroxine (T(4)), it was suggested that they may interfere with thyroid hormone metabolism and transport, e.g., by competition with T(4) on transthyretin (TTR). In the present study, we investigated the possible interaction of several brominated flame retardants with T(4) binding to TTR in an in vitro competitive binding assay, using human TTR and 125 I-T(4) as the displaceable radioligand. Compounds were tested in at least eight different concentrations ranging from 1.95 to 500 nM. In addition, we investigated the structural requirements of these and related ligands for competitive binding to TTR. We were able to show very potent competition binding for TBBPA and PBP (10.6- and 7.1-fold stronger than the natural ligand T(4), respectively). PBDEs were able to compete with T(4)-TTR binding only after metabolic conversion by induced rat liver microsomes, suggesting an important role for hydroxylation. Brominated bisphenols with a high degree of bromination appeared to be more efficient competitors, whereas chlorinated bisphenols were less potent compared to their brominated analogues. These results indicate that brominated flame retardants, especially the brominated phenols and tetrabromobisphenol A, are very potent competitors for T(4) binding to human transthyretin in vitro and may have effects on thyroid hormone homeostasis in vivo comparable to the thyroid-disrupting effects of PCBs.

Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

“…Hydroxylated PBDEs are found, for example, in fish such as salmon (Marsh et al 2004), and some may also have a natural origin. As said earlier, hydroxylated-PBDEs have a much greater affinity for TTR than PBDEs (Meerts et al 2000).…”

“…For example, most PBDEs have antiandrogenic activity in vitro and in vivo (Stoker et al 2005); tetra-to hexa-BDEs have potent estrogenic activity in vitro; heptaBDE and 6-OH-BDE-47, a metabolite of BDE-47, have anti-estrogenic activity (Hamers et al 2006). Hydroxylated BDEs are structurally very similar to thyroid hormones, and have been shown to displace thyroid hormones from the thyroxin plasma transporter transthyretin (TTR) (Meerts et al 2000). PBDEs have also been reported to decrease levels of total and free T 4 in adult animals (Fowles et al 1994;Hallgren et al 2001), and following developmental exposure (discussed below).…”

“…Meerts et al (2000) reported that several PBDEs could interact with TTR, one of the thyroid hormone-binding proteins in plasma, thereby displacing T 4 . However, such interaction only occurred in the presence of phenobarbital-treated microsomes (enriched in CYP 1A, 2B and 4A3), implicating one or more PBDE metabolites.…”

“…Furthermore, hydroxylated PCBs bind to TBG with much lower affinity than to TTR (Lans et al 1994), and the same may be true for hydrolated PBDEs. TTR may still facilitate the transport of OH-PBDEs in the brain (Meerts et al 2000), though it has been shown that TTR is not indispensable for T 4 entry into the brain (Palha, 2002). Biochemical studies on direct effects of PBDE on the developing brain have yet to provide convincing evidence of precise mechanisms, though some indications (e.g.…”

Toxicity of tetrabromobisphenol A (TBBPA) in zebrafish (Danio rerio) in a partial life-cycle test

“…LC 50 concentrations reported include 0.51 mg/l (0.9 M) in bluegill sunfish, 0.40 mg/l (0.7 M) in rainbow trout (WHO/IPCS 1995), and a relatively high 3 mg/l (5.5 M) in zebrafish (Lee et al 1993). Evidence for TBBPA toxicity at lower doses is limited and points to modulation of the thyroid and reproductive hormonal systems: TBBPA competes with the in vitro binding of thyroxin to its human plasma-transporter protein, transthyretin (Meerts et al 2000;Hamers et al 2004), and the rat thyroid receptor (Kitamura et al 2002), and increases the response to T3 in cultured GH3 rat pituitary adenoma cells (Kitamura et al 2005a). However, 10 −8 M (54 ng/l) TBBPA and higher may suppress T3-dependent tail shortening in Rana rugosa tadpoles, indicating anti-thyroid activity (Kitamura et al 2005b).…”