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Open Journal of Fisheries Research
Vol.03 No.03(2016), Article ID:18515,8 pages
10.12677/OJFR.2016.33006

Toxic Effects and Mechanism of 2,2',4,4'-Tetrabromodiphenyl Ether

Lili Su1, Weina Sun2, Xizhu Yan1*

1Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture, Fisheries College of Jimei University, Xiamen Fujian

2Comprehensive Outpatient Department of Jimei University, Xiamen Fujian

Received: Aug. 17th, 2016; accepted: Sep. 6th, 2016; published: Sep. 12th, 2016

Copyright © 2016 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

ABSTRACT

2,2',4,4'-tetrabromodiphenyl ether is one of the highest homologue of PBDEs in environmental media. It has lipophilic and bioaccumulation characteristics and can also produce physiological toxicity to organism even at low concentration. The paper introduces the main source and distribution in environment of BDE-47. The toxicity effects and mechanism of BDE-47 are illustrated from several aspects toxicity of reproductive, developmental, thyroid, neurotoxicity and immune.

Keywords:BDE-47, Reproductive and Developmental Toxicity, Hyroid Toxicity, Neurotoxicity, Immune Toxicity, Toxic Mechanism

2,2',4,4'-四溴联苯醚毒性效应及其致毒机理

宿丽丽1，孙维娜2，阎希柱1*

1集美大学水产学院，农业部东海海水健康养殖重点实验室，福建 厦门

2集美大学综合门诊部，福建 厦门

收稿日期：2016年8月17日；录用日期：2016年9月6日；发布日期：2016年9月12日

摘 要

2,2',4,4'-四溴联苯醚(tetrabromodiphenyl ether, BDE-47)是环境介质中含量最高的多溴联苯醚(PBDEs)同系物之一，具有亲脂性和生物易累积等特点，即使是较低浓度的胁迫，也会对生物体产生生理毒性。文章介绍了BDE-47在环境介质中的主要来源和分布，从生殖发育毒性、甲状腺毒性、神经毒性，免疫毒性等几个方面，阐述了BDE-47毒性效应及其致毒机理。

关键词 :BDE-47，生殖发育毒性，甲状腺毒性，神经毒性，免疫毒性，致毒机理

1. 引言

多溴联苯醚(polybrominated diphenyl ethers, PBDEs)是一类新型的溴化阻燃剂，阻燃效率高，热稳定性好，常被添加到树脂、聚苯乙烯和聚氨酯泡沫等高分子合成材料中，广泛地应用于电力行业家用电器等领域 [1] 。PBDEs作为阻燃剂是通过物理混合而不是化学键合作用，通电加热后很容易从聚合物中溶解或逸散出来，在电脑和电视机的使用过程中会因温度上升而使PBDEs释放到周围空气中 [2] 。此外，焚化含有PBDEs的废旧电子电气设备的拆卸及最终处理过程，也是PBDEs进入环境的主要途径 [3] 。BDE-47是PBDEs同系物之一，分布广、在生物体中含量高、毒性较强 [4] - [6] ，并且具有亲脂性和生物易累积等特点 [7] [8] 。BDE-47的主要污染来源是直接向水体中的排放，特别是一些电子废弃物地区，含量很高 [9] 。我国青岛近海 [10] 、长江下游及长江口沉积物中 [11] [12] 、天津大沽排污河口 [13] 的均已检测到PBDEs，珠三角地区的沉积物中BDE-47污染水平相对较高0.1~5.5 ng∙g−1 [14] [15] 。水中PBDEs的含量与沉积物相比较低，北美安大略湖表层水中PBDEs处于4~13 pg∙L−1水平，其中BDE-47和BDE-99共占了总量的90%以上 [16] 。周明莹等 [17] 对青岛胶州湾养殖水体中的PBDEs进行了调查，主要检测出BDE-47、BDE-17、BDE-85、BDE-99四种，并且BDE-47为主要的污染物，含量为183.5 pg∙L−1。

各地区BDE-47分布及含量，与该地区的地理环境和城市的结构有关，城市的垃圾处理及污水排放处，污染物的含量相对较高。BDE-47分布广，并且具有蓄积性和毒性，会对生物有机体造成损伤。本文结合近年来国内外的研究情况，着重讨论BDE-47的神经毒性、生殖毒性、甲状腺毒性、免疫毒性及其可能的致毒机制。

2. 生殖发育毒性

BDE-47能干扰生物体内生殖激素的分泌及信号转导，从而影响有机体的生殖与发育功能。研究表明，BDE-47及其主要代谢产物6-羟基-2,2',4,4'-四溴联苯醚(6-OH-BDE-47)，可与雌激素受体(estrogen receptors, ER)、雄激素受体(androgen receptors, AR)产生拮抗作用 [18] [19] 。同时，BDE-47还能与前雌激素(proestrogen)、雄性激素(estrogen)等产生拮抗或竞争作用 [20] - [22] ，还可以引起HCG含量变化从而减少孕酮(progesterone)分泌量和减少细胞内cAMP的含量 [23] 。

Fong等 [24] 将海水青鳉鱼(Oryzias melastigma)暴露于BDE-47，0.65和1.30 μg∙g−1每天两个剂量组，持续21天，结果显示在睾丸中有42个蛋白质差异表达，BDE-47会导致组蛋白变型体和小清蛋白规律性下降，从而阻碍精子发生和引起不育。在卵巢中有38个蛋白质差异表达，卵黄蛋白原的增加和载脂蛋白的表达，表明了BDE-47充当类雌激素化合物，导致海水青鳉鱼的生殖障碍。流行病学调查表明，男子的精子活动性与其血清中的BDE-47浓度呈负相关，BDE-47暴露可影响精子质量 [25] 。

张璟等 [26] 将褶皱臂尾轮虫(Branchionus plicatilis)分别暴露于0.05、0.1、0.2 mg∙L−1的BDE-47溶液中24小时，导致褶皱臂尾轮虫卵巢组织形态萎缩、脂质小滴数量减少。各浓度的BDE-47能极显著(P < 0.001)降低褶皱臂尾轮虫的产卵数与产幼数；0.1 mg∙L−1，0.2 mg∙L−1的BDE-47能极显著(P < 0.001)降低褶皱臂尾轮虫的孵化率。Yue等 [27] 研究也得出同样结论，将斑马鱼暴露于100和1000 μg∙L−1的BDE-47，诱导产卵率下降，影响产卵量，BDE-47处理组的繁殖力低于对照组，与最高剂量组成显著差异。雄性斑马鱼(Zebrafish)暴露在100和1000 μg∙L−1时，受精率会降低，但对孵化率没有影响。BDE-47暴露作用下，日本虎斑猛水蚤的发育时间明显延长；高浓度(10 mg∙L−1)的BDE-47明显抑制了日本虎斑猛水蚤(Tigriopus japonicus)10天和24天的存活数量；雌体产无节幼虫数明显减少，雌雄比下降 [28] 。当沉积物中BDE-47的浓度 ≥ 640 ng∙g−1时，铜锈环棱螺(Bellamya aeruginosa)的繁殖力下降50%，这进一步证实了BDE-47对水生生物的繁殖毒性 [29] 。Carlsson等 [30] 将非洲爪蟾(Xenopus laevis)暴露于BDE-47 14 d，蝌蚪后腿的长度发育减慢，体重下降、体长缩短，而且高浓度的BDE-47可以使非洲爪蟾死亡率上升。

3. 甲状腺毒性

BDE-47对甲状腺激素(thyroxine, TH)干扰作用的毒性机制目前还不是十分清楚，但已知可以通过以下两条途径干扰甲状腺激素：

第一条途径：BDE-47使小鼠肝脏尿苷二磷酸葡萄糖醛酸转移酶(UGT1A1)与硫酸转移酶(SULT1A1)，细胞色素CYP3A1、CYP2B10 mRNA表达上调，表明BDE-47可以诱导UGT1A1与SULT1A1表达，而CYP3A1、CYP2B1表达增强分别是受孕烷X受体(PXR)和组成型雄甾烷受体(CAR)被激活的标志物。因此BDE-47导致血清T3，T4降低的分子机制可能是BDE-47激活了核受体PXR和CAR，后者又诱导UGT1A1与SULT1A1的表达，导致UGT1A1与SULT1A1增加，加速其共同底物TH的葡萄糖醛酸化和硫酸脂化，使TH排泄加快，体内TH循环减少 [31] 。第二条途径：由于BDE-47的分子结构与甲状腺激素T3和T4非常相似，一些同类物可以增强、降低或模仿甲状腺激素的生物学作用，从而干扰甲状腺的正常功能 [32] 。

Vicki等 [33] 对雌性C57 BL/6小鼠(9周龄)进行持续4天的口服给药，BDE-47的剂量分别为3，10或100 mg∙kg−1每天。收集肝、肾和血清进行分析。BDE-47在100 mg∙kg−1每天会使T4显著下降至总浓度的43%。肝中T4-葡萄糖醛酸化作用没有增加，但UGT1A1，UGT1A7和Ugt2b5的表达量随着T4浓度减小显著增加。刘早玲等 [31] 用0.5，5，50 mg∙kg−1 BDE-47对小鼠进行染毒，小鼠血清中T4水平降低，中、高剂量染毒组T3水平降低，破坏了T4和T3的平衡。胡辛楠等 [34] 用BDE-47对HepG2细胞进行试验染毒，分为高，中，低三个剂量组，分别为100 μmol∙L−1、10 μmol∙L−1、1 μmol∙L−1。BDE-47是PXR受体的激活剂，可一定程度地激活PXR受体 [35] ，并同时增强其下游基因CYP3A4的转录活性，引起其下游Ⅰ相代谢酶CYP3A4、Ⅱ相代谢酶UGT1A3、SULT2A1基因的mRNA转录及其蛋白表达水平的增强。并且BDE-47能抑制TR两个受体亚型TRα1和TRβ1的mRNA转录及其蛋白的翻译水平。其抑制程度呈现一定的剂量-效应关系(P < 0.05)。因此，该实验得出PXR受体可能在BDE-47甲状腺毒性效应中发挥了重要的作用，并进一步抑制甲状腺激素两个重要功能性亚型受体的表达。

4. 神经毒性

BDE-47的神经毒性会损害生物体的感觉运动、学习与记忆、自主行为发育等。尤其是在生物体神经发育早期阶段，神经毒性表现的更为强烈。

一些神经细胞体外研究证实，BDE-47可能改变的细胞内氧化/抗氧化平衡，诱导氧化应激 [36] - [38] 。氧化应激是细胞凋亡级联反应中的始发因素，继而诱导神经细胞凋亡，引起神经元结构和功能的改变，产生神经毒性作用 [39] 。

除此之外，BDE-47进入生物体内会和胆碱酯酶AChE结合，无法分解乙酰胆碱，造成乙酰胆碱的积累，引起神经功能紊乱，甚至导致生物体死亡 [40] ；BDE-47可以干扰信号转导通路、细胞内信号，增加蛋白激酶C (protein kinase C, PKC)迁移，促进花生四烯酸(arachidonic acid, AA)释放，干扰神经元细胞内钙平衡 [41] ；还可导致突触囊泡摄取多巴胺减少，使内胞浆中多巴胺浓度增加，造成氧化损伤 [42] 。Frouin等 [43] 的研究结果表明，不同浓度的BDE-47，BDE-99和BDE-153均可诱导海豹(Seals)成体以及其嗜中性粒细胞(neutrophil granulocytes)内活性氧(Reactive oxygen species, ROS)含量的升高。体外实验同样发现，剂量为5 μM的BDE-47便会导致细胞ROS的含量显著升高 [44] 。Wang等 [45] 用低浓度的BDE-47 (10−10、10−9和10−8 mol∙L−1)对人类肝癌HepG2细胞进行染毒，结果表明，低浓度的BDE-47即能促进细胞增殖，但是DNA损伤或细胞凋亡没有明显变化，ROS胁迫组与对照组相比显著升高。Eriksson等 [46] [47] 将新生小鼠或大鼠暴露在多溴联苯醚(BDE-47, -99, -153, -183, -203, -206, -209)中，会导致自发运动持久的变化，主要是表征为多动或下降习惯，并扰乱学习和记忆能力。将围产期C57BL/6J小鼠暴露在0.03，0.1和1 mg∙kg−1每天的BDE-47中，三个暴露组中的老鼠在在巴恩斯迷宫中要更长的时间，走更远的距离才能找到逃生出口 [48] 。何卫红等 [49] 用BDE-47对体外原代培养的大鼠海马细胞进行染毒，实验表明，BDE-47可诱导海马细胞凋亡，导致神经细胞数量的减少而引起神经系统功能的异常。吉贵祥等 [50] 用0.5 mg∙L−1 BDE-47染毒斑马鱼幼鱼96 h后，0.5 mg∙L−1暴露组的幼鱼在眼部、脑部及脊髓部位呈现强烈的凋亡信号，具有组织特异性。当鱼体暴露在浓度为0.0125 mg∙L−1的BDE-47下，体内AChE活性明显被诱导，而在1.25 mg∙L−1的浓度下，AChE活性则被被显著抑制 [51] 。

5. 免疫毒性

生物体的免疫系统，可防止外来病原微生物或其他抗原异物的入侵而引起的内环境波动，保证机体的正常生理机能。若免疫功能亢进，会对自身器官或组织产生伤害；此功能下降，则会导致免疫系统的缺陷 [52] 。

BDE-47免疫毒性的研究主要集中于对陆生生物的研究，对海洋生物的研究较少。一方面BDE-47可以改变甲状腺激素(TH)的动态平衡而影响其免疫功能。另一方面，BDE-47及其代谢产物6-OH-BDE-47与T4的构象非常相似，通过置换T4与甲状腺素运载蛋白(transthyretin, TTR)结合，从而改变TH的代谢和传递 [53] [54] ；同时BDE-47可使粒细胞的吞噬作用减弱，中性粒细胞活性氧ROS堆积，免疫细胞巯基水平下降 [55] 。

Arkoosh等 [56] 将大马哈鱼(Salmon)经食物暴露于环境相关剂量(190 ng∙g−1食物)的PBDEs (含有BDE-47、BDE-99、BDE-100、BDE-153和BDE-154) 40 d后，对鳗利斯顿氏菌(Listonella anguillarum)感染的抵抗力下降。12 mol∙L−1的BDE-47、-99和-153同样能引起海豹天然免疫细胞-粒细胞的氧化胁迫，并导致其吞噬能力下降 [43] 。

6. 其他毒性

此外，BDE-47的胁迫会导致基因重组，引起癌症，但水生生物这方面的的毒性研究较少。Helleday等 [57] 研究了BDE-I、BDE-12和BDE-47对哺乳动物细胞内基因重组的影响，并与DDT和PCBS作对照。结果表明，基因重组频率显著地提高。这说明BDE-47可能具有潜在的致癌性。

Zhang [58] 用BDE-47处理小鼠12周后，发生较严重的肝脏损伤，血清转氨酶水平、肝脏绝对重量显著上升；肝脏细胞色素P450及UDP-葡萄糖醛酸转移酶(UDP-glucuronosyl transferase, GTUDPGT)升高；从而诱发肝细胞肥大、空泡化及坏死，这可能会引发小鼠肝脏肿瘤 [59] 。贾晓栋等 [60] 选取3个剂量组：80 μmol∙L−1、20 μmol∙L−1和5 μmol∙L−1的BDE-47对细胞进行染毒，BDE-47表现出了一定的细胞毒性。

7. 结论

2009年，PBDEs已被联合国列入《斯德哥尔摩公约》。PBDEs是一种新型持久性有机污染物，已经造成了全球性污染。由于其具有环境持久性，生物可累积性及对生物的毒害效应等特性，对其环境问题的研究已成为当前环境科学的一大热点。BDE-47作为PBDEs的同系物之一，对海洋生物影响的研究多集中在生物体内含量、分布的测定以及生理毒害等方面，但有一些致毒机制尚不很明确，需做进一步的研究。由于生态系统中环境毒物种类不断增加，多种环境毒物同时作用于机体普遍存在，BDE-47很可能与环境中存在的其他污染物产生联合毒性作用。因此，有必要开展有关BDE-47的联合毒性及其机制的研究。

基金项目

封闭海湾滩涂多毛类修复集成技术研究与示范，国家海洋公益性行业科研专项子课题(201205009-4)。

文章引用

宿丽丽,孙维娜,阎希柱. 2,2',4,4'-四溴联苯醚毒性效应及其致毒机理
Toxic Effects and Mechanism of 2,2',4,4'-Tetrabromodiphenyl Ether[J]. 水产研究, 2016, 03(03): 34-41. http://dx.doi.org/10.12677/OJFR.2016.33006

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