State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University , Nanjing 210023, PR China.
Multiphase Chemistry Department, Max Planck Institute for Chemistry , 55128 Mainz, Germany.
Environ Sci Technol. 2016 Nov 15;50(22):12429-12438. doi: 10.1021/acs.est.6b02029. Epub 2016 Oct 25.
Some hydroxylated polybrominated diphenyl ethers (HO-PBDEs), that have been widely detected in the environment and tissues of humans and wildlife, bind to thyroid hormone (TH) receptor (TR) and can disrupt functioning of systems modulated by the TR. However, mechanisms of TH disrupting effects are still equivocal. Here, disruption of functions of TH modulated pathways by HO-PBDEs was evaluated by assays of competitive binding, coactivator recruitment, and proliferation of GH3 cells. In silico simulations considering effects of coregulators were carried out to investigate molecular mechanisms and to predict potencies for disrupting functions of the TH. Some HO-PBDEs were able to bind to TR with moderate affinities but were not agonists. In GH3 proliferation assays, 13 out of 16 HO-PBDEs were antagonists for the TH. In silico simulations of molecular dynamics revealed that coregulators were essential for identification of TH disruptors. Among HO-PBDEs, binding of passive antagonists induced repositioning of H12, blocking AF-2 (transactivation function 2) and preventing recruitment of the coactivator. Binding of active antagonists exposed the coregulator binding site, which tended to bind to the corepressor rather than the coactivator. By considering both passive and active antagonisms, anti-TH potencies of HO-PBDEs could be predicted from free energy of binding.
一些羟基化多溴二苯醚（HO-PBDEs）已广泛存在于人类和野生动物的环境和组织中，它们与甲状腺激素（TH）受体结合，并能干扰受 TR 调节的系统的功能。然而，TH 破坏作用的机制仍存在争议。在这里，通过 GH3 细胞的竞争性结合、辅激活因子募集和增殖试验，评估了 HO-PBDEs 对 TH 调节途径功能的破坏作用。考虑到共调节剂的影响，进行了计算机模拟，以研究分子机制并预测对 TH 功能破坏的效力。一些 HO-PBDEs 能够与 TR 以中等亲和力结合，但不是激动剂。在 GH3 增殖试验中，16 种 HO-PBDE 中有 13 种对 TH 表现为拮抗剂。分子动力学的计算机模拟揭示了共调节剂对于鉴定 TH 破坏剂是必不可少的。在 HO-PBDEs 中，被动拮抗剂的结合导致 H12 的重新定位，阻断 AF-2（转录激活功能 2）并阻止辅激活因子的募集。活性拮抗剂的结合暴露了共调节剂结合位点，该位点倾向于与核受体抑制因子而不是辅激活因子结合。通过考虑被动和主动拮抗作用，可以根据结合自由能预测 HO-PBDEs 的抗 TH 效力。
