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 [$\text{TR}\mathrm{\alpha }$ ligand-binding domain (LBD) and $\text{TR}\mathrm{\beta }\text{-LBD}$] 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 $0.1\mathrm{\mu }\mathrm{M}$ to $1.0\mathrm{\mu }\mathrm{M}$ but did not bind to TBG. They also bound to both subtypes of TR-LBDs with 20% maximal inhibitory concentrations ranging from $4.0\mathrm{\mu }\mathrm{M}$ to $50.0\mathrm{\mu }\mathrm{M}$. 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 $0.3\mathrm{\mu }\mathrm{M}$ to $2.5\mathrm{\mu }\mathrm{M}$] and further enhanced TH-induced GH3 cell proliferation (with LOECs ranging from $0.3\mathrm{\mu }\mathrm{M}$ to $1.2\mathrm{\mu }\mathrm{M}$). 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

中文翻译：

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四溴双酚A单醚结构类似物与甲状腺激素转运蛋白和受体的结合和活性。

摘要

背景：

四溴双酚A（TBBPA）单醚结构类似物，被确定为商业TBBPA双醚衍生物的副产物或转化产物，已被确定为新兴的广泛污染物。但是，关于其毒理作用的信息很少。

目的：

我们旨在探讨潜在的甲状腺激素（TH）系统对TBBPA单醚结构类似物的破坏作用。

方法：

化学物质对人TH转运蛋白[运甲状腺素蛋白（TTR）和甲状腺素结合球蛋白（TBG）]和受体的结合力[$\text{TR}\mathrm{\alpha }$ 配体结合域（LBD）和 $\text{TR}\mathrm{\beta }\text{-LBD}$通过荧光竞争性结合测定法测定。分子对接用于模拟化学物质与蛋白质的结合模式。通过GH3细胞增殖测定法评估化学物质的破坏细胞TR的能力。化学物质的细胞内浓度通过高效液相色谱和质谱法测量。

结果：

与TTR结合的TBBPA单醚结构类似物的最大抑制浓度为 $0.1\mathrm{\mu }\mathrm{中号}$ 至 $1.0\mathrm{\mu }\mathrm{中号}$但未绑定到TBG。它们还与TR-LBD的两种亚型结合，最大抑制浓度为20％$4.0\mathrm{\mu }\mathrm{中号}$ 至 $50.0\mathrm{\mu }\mathrm{中号}$。对接结果表明，类似物以与TBBPA相似的结合模式装配到TTR和TR-LBD的配体结合口袋中。这些化合物可能通过TR诱导GH3细胞增殖[最低有效浓度（LOECs）为$0.3\mathrm{\mu }\mathrm{中号}$ 至 $2.5\mathrm{\mu }\mathrm{中号}$]，并进一步增强TH诱导的GH3细胞增殖（LOEC范围从 $0.3\mathrm{\mu }\mathrm{中号}$ 至 $1.2\mathrm{\mu }\mathrm{中号}$）。与TBBPA相比，TBBPA-单（2,3-二溴丙基醚）的GH3细胞增殖作用高4.18倍，细胞膜转运能力高105倍。

结论：

这项研究提供了可能的机制，潜在的新型TBBPA结构类似物在TTR或TR结合方面的差异。这些化合物可能通过破坏循环中的TH转运和TH反应性细胞的TR活性而发挥TH系统破坏作用。https://doi.org/10.1289/EHP6498