Binding and Activity of Tetrabromobisphenol A Mono-Ether Structural Analogs to Thyroid Hormone Transport Proteins and Receptors.

ABSTRACT: BACKGROUND:Tetrabromobisphenol A (TBBPA) mono-ether structural analogs, identified as the by-products or transformation products of commercial TBBPA bis-ether derivatives, have been identified as emerging widespread pollutants. However, there is very little information regarding their toxicological effects. OBJECTIVE:We aimed to explore the potential thyroid hormone (TH) system-disrupting effect of TBBPA mono-ether structural analogs. METHODS:The binding potencies of chemicals toward human TH transport proteins [transthyretin (TTR) and thyroxine-binding globulin (TBG)] and receptors [TR? ligand-binding domain (LBD) and TR?-LBD] were determined by fluorescence competitive binding assays. Molecular docking was used to simulate the binding modes of the chemicals with the proteins. The cellular TR-disrupting potencies of chemicals were assessed by a GH3 cell proliferation assay. The intracellular concentrations of the chemicals were measured by high-performance liquid chromatography and mass spectrometry. RESULTS:TBBPA mono-ether structural analogs bound to TTR with half maximal inhibitory concentrations ranging from 0.1?M to 1.0?M but did not bind to TBG. They also bound to both subtypes of TR-LBDs with 20% maximal inhibitory concentrations ranging from 4.0?M to 50.0?M. The docking results showed that the analogs fit into the ligand-binding pockets of TTR and TR-LBDs with binding modes similar to that of TBBPA. These compounds likely induced GH3 cell proliferation via TR [with the lowest effective concentrations (LOECs) ranging from 0.3?M to 2.5?M] and further enhanced TH-induced GH3 cell proliferation (with LOECs ranging from 0.3?M to 1.2?M). Compared with TBBPA, TBBPA-mono(2,3-dibromopropyl ether) showed a 4.18-fold higher GH3 cell proliferation effect and 105-fold higher cell membrane transportation ability. CONCLUSION:This study provided a possible mechanism underlying the difference in TTR or TR binding by novel TBBPA structural analogs. These compounds might exert TH system-disrupting effects by disrupting TH transport in circulation and TR activity in TH-responsive cells. https://doi.org/10.1289/EHP6498.

SUBMITTER: Ren XM 

PROVIDER: S-EPMC7584160 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature