梁峰;穆云松;李会仙;冯承莲;

• 1:河南城建学院市政与环境工程学院
• 2:中国环境科学研究院环境基准与风险评估国家重点实验室

摘要(Abstract)：

近年来,羟基多溴代二苯醚(OH-PBDEs)的类甲状腺素效应逐渐引起人们的关注,然而其结构效应关系和致毒机制尚不清楚。甲状腺激素结合球蛋白(TBG)和运甲状腺素蛋白(TTR)是人体转运甲状腺素的重要蛋白,通过计算毒理学手段可以揭示OH-PBDEs的微观毒理机制。利用分子对接技术研究OH-PBDEs与TBG、TTR的结合模式和构象特征,识别关键氢键氨基酸为赖氨酸Lys270(TBG),亮氨酸Leu110(TTR)和丝氨酸Ser117(TTR)。基于活性构象特征,构建14种典型OH-PBDEs的3D-QSAR模型,定量预测OH-PBDEs与TBG、TTR的结合亲和力。最佳预测模型的相关系数r2分别为0.966(TBG)和0.961(TTR),抽一法交叉验证相关系数q2分别为0.560(TBG)和0.525(TTR)。研究发现,OH-PBDEs的静电和氢键作用可增强结合亲和力,分别贡献65.4%(TBG)和68.7%(TTR)。研究结果为揭示OH-PBDEs与甲状腺素转运蛋白的相互作用提供新视角,有助于全面评价OH-PBDEs对人体甲状腺素调节功能的损伤。

关键词(KeyWords)： 羟基多溴代二苯醚;甲状腺素结合球蛋白;运甲状腺素蛋白;竞争抑制;比较分子场分析;比较相似性指数分析

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金面上项目(41673087);; 河南省科技攻关计划项目(162102310389);; 河南省教育厅科学技术研究重点项目(14A610012)

作者(Author): 梁峰;穆云松;李会仙;冯承莲;

Email:

参考文献(References)：

• [1]Costa L G,de Laat R,Tagliaferri S,et al.A mechanistic view of polybrominated diphenyl ether(PBDE)developmental neurotoxicity[J].Toxicology Letters,2014,230:282-294
• [2]Wang H,Zhang Y,Liu Q,et al.Examining the relationship between brominated flame retardants(BFR)exposure and changes of thyroid hormone levels around e-waste dismantling sites[J].International Journal of Hygiene and Environmental Health,2010,213:369-380
• [3]Darnerud P O,Eriksen G S,Johannesson T,et al.Polybrominated diphenyl ethers:Occurrence,dietary exposure,and toxicology[J].Environmental Health Perspectives,2001,109:49-68
• [4]Letcher R J,Bustnes J O,Dietz R,et al.Exposure and effects assessment of persistent organohalogen contaminants in arctic wildlife and fish[J].Science of the Total Environment,2010,408:2995-3043
• [5]Gabrielsen K M,Krokstad J S,Villanger G D,et al.Thyroid hormones and deiodinase activity in plasma and tissues in relation to high levels of organohalogen contaminants in East Greenland polar bears(Ursus maritimus)[J].Environmental Research,2015,136:413-423
• [6]Dahlberg A K,Chen V L,Larsson K,et al.Hydroxylated and methoxylated polybrominated diphenyl ethers in long-tailed ducks(Clangula hyemalis)and their main food,Baltic blue mussels(Mytilus trossulus x Mytilus edulis)[J].Chemosphere,2016,144:1475-1483
• [7]Sjodin A,Hagmar L,Klasson-Wehler E,et al.Flame retardant exposure:Polybrominated diphenyl ethers in blood from Swedish workers[J].Environmental Health Perspectives,1999,107:643-648
• [8]Wiseman S B,Wan Y,Chang H,et al.Polybrominated diphenyl ethers and their hydroxylated/methoxylated analogs:Environmental sources,metabolic relationships,and relative toxicities[J].Marine Pollution Bulletin,2011,63:179-188
• [9]Nost T H,Helgason L B,Harju M,et al.Halogenated organic contaminants and their correlations with circulating thyroid hormones in developing Arctic seabirds[J].Science of the Total Environment,2012,414:248-256
• [10]Hallgren S,Sinjari T,Hakansson H,et al.Effects of polybrominated diphenyl ethers(PBDEs)and polychlorinated biphenyls(PCBs)on thyroid hormone and vitamin A levels in rats and mice[J].Archives of Toxicology,2001,75:200-208
• [11]Zhou T,Taylor M M,De Vito M J,et al.Developmental exposure to brominated diphenyl ethers results in thyroid hormone disruption[J].Toxicological Sciences,2002,66:105-116
• [12]Eriksson P,Jakobsson E,Fredriksson A.Brominated flame retardants:A novel class of developmental neurotoxicants in our environment?[J].Environmental Health Perspectives,2001,109:903-908
• [13]Hallgren S,Darnerud P O.Polybrominated diphenyl ethers(PBDEs),polychlorinated biphenyls(PCBs)and chlorinated paraffins(CPs)in rats-testing interactions and mechanisms for thyroid hormone effects[J].Toxicology,2002,177:227-243
• [14]Larsson M,Pettersson T,Carlstrom A.Thyroid-hormone binding in serum of 15 vertebrate species-isolation of thyroxine-binding globulin and prealbumin analogs[J].General and Comparative Endocrinology,1985,58:360-375
• [15]Savu L,Vranckx R,Maya M,et al.Thyroxine-binding globulin and thyroxine-binding prealbumin in hypothyroid and hyperthyroid developing rats[J].Biochimica et Biophysica Acta,1989,992:379-384
• [16]Meerts I A T M,Zanden J J V,Luijks E A C,et al.Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro[J].Toxicological Sciences:An Official Journal of the Society of Toxicology,2000,56:95-104
• [17]Hamers T,Kamstra J H,Sonneveld E,et al.Biotransformation of brominated flame retardants into potentially endocrine-disrupting metabolites,with special attention to 2,2',4,4'-tetrabromodiphenyl ether(BDE-47)[J].Molecular Nutrition&Food Research,2008,52:284-298
• [18]Murk A J,Rijntjes E,Blaauboer B J,et al.Mechanism-based testing strategy using in vitro approaches foridentification of thyroid hormone disrupting chemicals[J].Toxicology in Vitro,2013,27:1320-1346
• [19]Legler J,Brouwer A.Are brominated flame retardants endocrine disruptors?[J].Environment International,2003,29:879-885
• [20]易忠胜,李连臣,叶廷文,等.羟基多溴二苯醚生物活性的QSAR研究[J].桂林理工大学学报,2011,31:430-438Yi Z S,Li L C,Ye T W,et al.QSAR study on bioactivity of hydroxylated polybrominated diphenyl ethers[J].Journal of Guilin University of Technology,2011,31:430-438(in Chinese)
• [21]Cao J,Lin Y,Guo L H,et al.Structure-based investigation on the binding interaction of hydroxylated polybrominated diphenyl ethers with thyroxine transport proteins[J].Toxicology,2010,277:20-28
• [22]Yang W H,Shen S D,Mu L L,et al.Structure-activity relationship study on the binding of PBDEs with thyroxine transport proteins[J].Environmental Toxicology and Chemistry,2011,30:2431-2439
• [23]Yang X H,Xie H B,Chen J W,et al.Anionic phenolic compounds bind stronger with transthyretin than their neutral forms:Nonnegligible mechanisms in virtual screening of endocrine disrupting chemicals[J].Chemical Research in Toxicology,2013,26:1340-1347
• [24]杨先海,陈景文,李斐.化学品甲状腺干扰效应的计算毒理学研究进展[J].科学通报,2015,60:1761-1770Yang X H,Chen J W,Li F.Progress in computational toxicology for evaluation of thyroid disrupting effects of chemicals[J].Chinese Science Bulletin,2015,60:1761-1770(in Chinese)
• [25]Zhou A W,Wei Z Q,Read R J,et al.Structural mechanism for the carriage and release of thyroxine in the blood[J].Proceedings of the National Academy of Sciences of the United States of America,2006,103:13321-13326
• [26]Wojtczak A,Neumann P,Cody V.Structure of a new polymorphic monoclinic form of human transthyretin at 3angstrom resolution reveals a mixed complex between unliganded and T-4-bound tetramers of TTR[J].Acta Crystallographica Section D-Biological Crystallography,2001,57:957-967
• [27]Topliss J G,Costello R J.Chance correlations in structure-activity studies using multiple regression-analysis[J].Journal of Medicinal Chemistry,1972,15:1066-1068
• [28]Golbraikh A,Tropsha A.Beware of q2![J].Journal of Molecular Graphics and Modelling,2002,20:269-276