有机磷酸酯对甲状腺激素的破坏由核/膜甲状腺激素受体介导：体外、体内和计算机研究,Environmental Science & Technology

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有机磷酸酯对甲状腺激素的破坏由核/膜甲状腺激素受体介导：体外、体内和计算机研究
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2022-03-09 , DOI: 10.1021/acs.est.1c05956
Jian Li ₁ , Ying Xu ₁ , Na Li ₂ , Rui Zuo ₁ , Yuanzheng Zhai ₁ , Haiyang Chen ₁

Affiliation

早期对许多禁用阻燃剂 (FRs) 的机理研究强调了它们通过核甲状腺激素受体 (nTRs) 破坏甲状腺激素的活性，而一些替代 FRs，如有机磷酸酯 (OPEs) 则表现出较弱的 nTR 破坏作用。然而，越来越多的研究表明，OPEs 也发挥甲状腺激素干扰作用，其潜在机制尚不清楚。在此，使用综合体外、体内和计算机分析研究了 8 种典型 OPE 的甲状腺激素破坏作用和机制。所有测试的化学物质都与膜甲状腺激素受体 (mTR) 竞争性结合 [20% 相对抑制浓度 (RIC20): (3.5 ± 0.2) × 10 ¹至 (4.9 ± 1.0) × 10 ⁷ nM]，并且 Cl-OPEs 和烷基-OPEs 具有较低的 RIC20 值。^{相比之下，只有 4 个 OPE 在较高浓度 [≥ (4.8 ± 0.8) × 10 3} nM]下显示出 nTR 拮抗活性。Cl-OPEs 和烷基-OPEs 优先与 mTR 相互作用。分子对接表明 OPE 与 mTR 对接，这与竞争性结合分析一致。斑马鱼胚胎发育的体内分析证实三(1,3-二氯-2-丙基)磷酸盐诱导蛋白质的不适当表达，根据定量蛋白质组学分析，这些蛋白质相互作用可能与mTR有关。基于这些结果，mTR 可能在介导 OPE 的甲状腺激素破坏作用中发挥关键作用。

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Thyroid Hormone Disruption by Organophosphate Esters Is Mediated by Nuclear/Membrane Thyroid Hormone Receptors: In Vitro, In Vivo, and In Silico Studies

Earlier mechanistic studies of many prohibited flame retardants (FRs) highlighted their thyroid hormone-disrupting activity through nuclear thyroid hormone receptors (nTRs), whereas some alternative FRs such as organophosphate esters (OPEs) exerted weak nTR-disrupting effects. However, an increasing number of studies have revealed that OPEs also exert thyroid hormone-disrupting effects, and the underlying mechanism is unclear. Herein, the thyroid hormone-disrupting effects and mechanisms of 8 typical OPEs were investigated using integrated in vitro, in vivo, and in silico assays. All tested chemicals competitively bound to the membrane thyroid hormone receptor (mTR) [the 20% relative inhibitory concentration (RIC20): (3.5 ± 0.2) × 10¹ to (4.9 ± 1.0) × 10⁷ nM], and Cl-OPEs and alkyl-OPEs had lower RIC20 values. In contrast, only 4 OPEs showed nTR antagonistic activities at higher concentrations [≥ (4.8 ± 0.8) × 10³ nM]. Cl-OPEs and alkyl-OPEs preferentially interacted with mTR. Molecular docking illustrated that OPEs docked into mTRs, consistent with the competitive binding assay. In vivo analyses of zebrafish embryonic development confirmed that tris(1,3-dichloro-2-propyl) phosphate induced inappropriate expression of proteins, and these protein interactions might be associated with mTR according to the quantitative proteomic analysis. Based on the results, mTR might play a critical role in mediating the thyroid hormone-disrupting effects of OPEs.

更新日期：2022-03-09

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