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2018, 35(5):460-470.doi:10.13213/j.cnki.jeom.2018.17516

镉对生命活动的毒作用机制


1. 国立雅罗斯拉夫大学, 俄罗斯 雅罗斯拉夫 150003 ;
10. 台湾大学, 台湾 10617 ;
11. 台北医学大学万芳医院职业医学科, 台湾 10675 ;
12. 湖南农业大学动物科学技术学院, 湖南 长沙 410128 ;
13. 联合国教科文组织微量元素研究所, 法国 里昂 69000 ;
14. 国立奥伦堡大学, 俄罗斯 奥伦堡 460000 ;
2. 俄罗斯科学院细胞与细包共生研究所, 俄罗斯 奥伦堡 460001 ;
3. RUDN 大学, 俄罗斯 莫斯科, 117198 ;
4. 国立奥伦堡教育大学, 俄罗斯 奥伦堡 460000 ;
5. 黑得马克应用科学大学, 挪威 艾佛伦 2411 ;
6. 英兰德信托医院研究部, 挪威 布鲁门达 2380 ;
7. 保加利亚科学院实验形态学、病理学与人类学学院暨博物馆, 保加利亚 索非亚 1113 ;
8. 索非亚大学医学系, 保加利亚 索非亚 1113 ;
9. 营养与环境医学咨议会, 挪威 莫伊拉娜 8602

收稿日期: 2017-08-16;  发布日期: 2018-07-06

通信作者: AlexeyA.TINKOV, Email: tinkov.a.a@gmail.com  

作者简介: Alexey A.TINKOV (1989-), 男, 博士, 主治医师; 研究方向:环境毒理学

镉是一种众所周知的环境毒物,对人体健康有重大危害。镉与众多疾病相关,例如癌症、神经退化性疾病和代谢综合征等。虽然疾病种类各异,但是都与镉的化学性质和毒作用机制有关。镉易与含硫氮功能基结合,从而取代金属酶内的必需元素锌。镉的促炎症效应伴随促炎因子[肿瘤坏死因子(TNF-α)、白介素(IL)-1、IL-6]的大量产生和抗炎因子(IL-1拮抗剂、IL-4、IL-6、IL-10、IL-13)的明显减少,并且镉的促炎症活性与其通过各种途径所诱导的氧化应激紧密相关。镉还能取代各种蛋白质内的铁铜原子,从而增加自由氧化还原反应的活性金属库,激活芬顿(Fenton)反应;反之,镉对电子传递链的抑制损害了对氧气的利用,增加了活性氧的产生。最后,镉对抗氧化酶的抑制加剧自由基对核酸等生物大分子的损伤,引起遗传毒性并改变基因调控。因此,干扰镉的毒作用机制是预防镉暴露不良健康效应的有效措施。

关键词: 镉;  氧化应激;  毒性;  炎症;  遗传毒性 

工业的蓬勃发展导致重金属排放剧增并加剧了环境污染[1]。因为各种毒作用机制, 即使低剂量的重金属暴露也可能带来健康危害[2], 引起癌症、神经退化性疾病和其他代谢综合征等疾病。重金属的暴露途径包括饮食[3]、粉尘吸入[4]、空气污染[5]以及饮用水[6]等。

镉是对人体健康危害最大的重金属之一。环境中的镉污染一部分来自火山喷发, 将地球内部的镉带入生物层, 另一部分与迅猛的工业发展有关, 主要来自镍镉电池厂的排放与废弃物处理地的污染[7]。中国是最大的镉生产国之一, 近年来镉排放量大幅增加, 1990—2010年, 由474 t增加到2 186 t, 其中77%来自非铁金属冶炼工业[8]。2007年, 全球镍镉电池制造占镉工业总用量的83%, 回收再利用量约为产量的18% [9]

许多研究表明, 饮食与吸烟是镉暴露的主要来源。镉在泥土、饮用水与食物中广泛存在[10], 在全球大部分地区, 食物是不吸烟者最主要的镉暴露来源[11]。食物中的镉一部分来自大自然, 例如大气沉降[12-13], 另一个重要来源是化学肥料[14-15], 这取决于磷灰矿中的镉是否在肥料制造过程中被去除[16-17]。饮用水中的镉通常只占每日摄取量的一小部分[18]。虽然吸入镉对总的身体负担贡献很低[19], 但是金属工业区附近的水与空气可能遭到污染, 同时污染区泥土可能成为室内扬尘而导致镉暴露[20]。另外, 烟叶含镉, 吸烟是重要的镉暴露来源[21]。一根香烟含1~2 μg镉, 吸烟时约10%的镉进入人体, 其中50%在肺部吸收, 随血液分布至全身[22]。大多数国家人们每周自食物摄入0.7~2.8 μg/kg (以每kg体重计)镉, 低于世界卫生组织与联合国粮农组织建议的每周最大摄入量7 μg/kg [23], 部分人群的镉摄入量较高, 例如素食与嗜食海鲜者, 肾病患者与吸烟者的摄入量也可能超标。低铁状态等因素会影响镉的生物利用度、滞留与毒性[22, 24]。缺乏铁质者, 如孕妇、新生儿以及幼儿对镉的摄入增加。此外, 镉对人体的毒性也与锌和硒的摄入有关[24-27]。镉吸收后与金属硫蛋白结合, 然后运送至肝脏, 主要蓄积在肾脏, 肾镉的半衰期长达10~30年。本篇综述旨在深入探讨镉对生命活动的毒作用机制。

1   镉的理化性质

镉的反应性强, 不像汞容易形成稳定的有机金属化合物[28], 因此较少存在环境中。地壳中的镉质量百分比约1.1×10-5%, 常与锌并存。镉与硫的亲和性强, 主要以硫矿物形式存在。已知的镉矿物有硫化镉与碳酸镉, 镉也存在于页岩与黏土砂岩中。工业上的镉主要来自锌矿冶炼的副产品, 其中的锌原子被镉所取代[29]30锌、80汞、48镉同属元素周期表第十二族, 表 1列举镉的若干理化特性。

表1

镉的理化特性

镉在某些化合物中以配位数4的方式存在, 例如[Cd (NH3)4]2+与[Cd (CN)4]2- [30-31]。镉的特性之一是与比水柔软的配位基结合, 例如氨、胺、卤化物以及含硫或硫氢基的有机配体[32-36], 此类化合物性质稳定; 从晶场理论来看, 他们因d10组态而具备负稳定能量。在硫化物中硫原子作为电子供体, 最明显的例子即简单有机硫化物R1-S-R2, 配位基通过硫原子与络合剂结合。依据重金属与含硫配位基结合的稳定度来排序, 得到以下顺序: Hg2+>Pb2+>Cd2+ [37]。镉也能够与多糖类、腐殖酸、氨基酸形成化合物。α氨基酸、组氨酸和半胱氨酸与镉结合的能力最强, 这与镉离子对含硫氮配位基的亲和性一致[38-43]。二价镉离子与蛋白质中的硫基、巯基相互作用, 使得镉与多肽中的氨基酸形成了稳定的五环结构, 最终使氨基与羧基的功能受阻, 这也是镉高毒性的原因之一。此外, 镉还能与核酸磷酸基相互作用[44]

由于化学性质相近, 镉与锌常在矿石中并存, 依据皮尔逊酸(Pearson’s acid)理论, 镉属于较弱的皮尔逊酸。在含硫氰离子化合物中, 镉与汞通过硫原子与配位基结合, 例如[Cd (SCN)4]2-, 而锌却是通过氮原子, 形成[Zn (NCS)4]2-等结构[45-47]。镉能够取代体内酶活性中心的锌, 使其丧失功能。锌化合物属两性, 而镉化合物呈碱性多些。锌能减轻镉毒性, 是由于两种金属竞争酶活性中心, 如以下反应式所示[48-49]: ZnL+Cd2+↔CdL+Zn2+。这个反应式的平衡移动取决于镉锌化合物的稳定常数, 当β (ZnL) < β (CdL)时, 发生正向反应, 镉取代化合物中的锌。因此, 一般认为镉毒性的重要机制在于结合含硫氮官能基团, 并取代酶活性中心的必需元素[50-51]。NORDBERG等[52]和NORDBERG等[53]详细探讨了镉如何取代金属硫蛋白中的锌以及该蛋白对镉毒作用的保护效应。

2   镉与炎症反应的关系

炎症是对抗外源性化学物质的天然防御机制。研究[54-55]显示, 镉暴露激活特定细胞(例如肝脏Kupffer细胞), 引起白细胞浸润, 并增强单核与巨噬细胞释放促炎症与抗炎症因子。实验[54]显示, 将镉注入腹腔能增加血中白细胞CD11b的表达、细胞内髓过氧化酶活性以及活性氧氮自由基水平。日本研究者发现, 镉能引起急性系统性炎症, 延迟粒细胞集落刺激因子的产生, 导致长时间的嗜中性粒细胞增多症[56], 推测镉对细胞因子的效应取决于细胞形态与免疫细胞的激活状态。镉暴露所引起的炎症生物指标往往与各种疾病相关, 例如血镉与尿激酶型纤溶酶原激活物受体呈正相关, 血镉上升导致促炎症生物指标增加以及嗜中性粒细胞对淋巴细胞的比率升高[57]

2.1   镉对促炎症细胞因子的影响

镉在微摩尔浓度范围(1~10 μmol/L)即能表现促炎症特性[58]。白细胞介素(interleukin, IL)是炎症、免疫反应以及组织破坏的关键介质。暴露于外源性化学物质后, 细胞内IL-1a浓度升高, 抑制金属硫蛋白的表达[59]。用镉处理正常细胞与A549肺癌细胞后, IL-1a的表达水平升高[60]。细胞芯片分析显示, 暴露于氯化镉的A549细胞能上调19种、下调8种细胞因子[61]。接触氯化镉的骨骼肌肉细胞同样上调IL-6与肿瘤坏死因子α (tumor necrosisfactor α, TNF-α) [62]。染毒大鼠血浆中的IL-6、TNF-α浓度与过氧化氢酶、超氧化物歧化酶以及总抗氧化水平呈负相关[63], 血清细胞活素IL-1β与IL-10也增加, 但IFN-γ却减少[64]。IL-1、IFN-γ与TNF-α诱导内皮细胞表达黏附分子, 使白细胞黏附于内皮细胞, 从而促进炎症。此外, 镉在鼠科动物巨噬细胞中也上调IL-1与趋化因子CXCL1 [65]

IL-8是另一个与镉相关的促炎症细胞因子, 负责调度白细胞与巨噬细胞进入发炎处。研究[66]表明, 镉染毒后的人与鼠肺表皮细胞能通过丝裂原活化蛋白激酶细胞外信号调节激酶1/2依赖性途径(mitogenactivated protein kinase extracellular signal-regulated kinase 1/2-dependent pathway)激活IL-8的产生。许多研究也表明镉染毒后, 肝细胞[67]、外周血单核细胞[68]中IL-8的产生均增加。

2.2   镉对抗炎症细胞因子的影响

抗炎症细胞因子能够下调促炎症细胞因子的产生, 主要的抗炎症细胞因子包括IL-1受体拮抗剂(IL-1ra)、IL-4、IL-6、IL-10、IL-13以及细胞转化因子β (transforming growth factor β, TGF-β)。长久以来IL-6被视为促炎症细胞因子, 然而与镉对IL-6表达影响的研究结果并不一致[69]。研究表明, 10 μmol/L镉能抑制鼠类巨噬细胞中IL-6与IL-10的表达[65]。IL-10是重要的抗炎症细胞因子, 能抑制单核与巨噬细胞分泌促炎症细胞因子。分别用0、50、100、150 μmol/L氯化镉处理A549肺癌细胞6、12、18、24 h, 发现IL-10的表达水平在50 μmol/L镉暴露12 h时达到最大, 此后随着氯化镉浓度的升高、暴露时间的加长而降低[60]。抗炎症细胞因子IL-10的水平高于促炎症细胞因子IL-1α, 可能是氯化镉毒性的原因之一。研究也发现IL-10通过减少核因子κB (NF-κB)的易位介入细胞死亡过程[70]。IL-10研究结果和IL-6的一样存在矛盾, 例如究竟是加重还是减轻了炎症, 这个现象可能与镉的剂量有关。俄罗斯研究人员MEERSON提出“适应-去适应理论” (adaptation-deadaptation)来解释这一现象[71]。低剂量镉暴露能诱导身体防御机制如细胞因子与超氧化物歧化酶, 减轻炎症与氧化应; 但在高剂量暴露时防御机制被超越, 导致炎症增加与超氧化物歧化酶活性耗尽。

3   镉与氧化应激

3.1   镉毒作用的活性氧产生机制

镉毒作用的机制之一是产生活性氧, 在靶器官引起氧化应激效应[72-73]。镉引起氧化应激的第一条途径是取代细胞质蛋白中的铜与铁, 铜铁离子通过芬顿反应引起氧化应激[74]; 第二条途径是抑制电子传递链, 研究[75]表明, 镉能降低雄性豚鼠肝、脑、心线粒体内复合体Ⅱ与Ⅲ的活性, 通过与复合体Ⅲ中的半醌和细胞色素b结合以抑制电子传递链。不稳定的半醌堆积, 将电子泄漏给氧分子而产生超氧阴离子自由基。镉对巯基的亲和性高, 能消耗抗氧化清除剂, 如谷胱甘肽[76]。谷胱甘肽在肝脏中存量丰富, 通过直接反应起清除作用, 或者通过谷胱甘肽过氧化物酶系统对活性氧水平进行调节, 而急性镉暴露会消耗各器官的谷胱甘肽水平[77]。研究[78]表明, 利用顺丁烯二酸二乙酯降低肝内谷胱甘肽水平之后, 镉产生的α(- 4-吡啶基-1-氧)-N-叔丁基硝基酮在胆汁中明显增加, 说明谷胱甘肽系统受到干扰可能是镉所导致氧化应激的重要因素。慢性镉暴露能刺激合成, 从而增加组织中谷胱甘肽水平[79-81]。此外, 镉能改变超氧化物歧酶、过氧化氢酶、谷胱甘肽过氧化物酶的活性[74], 而超氧化物歧酶和过氧化氢酶被视为对抗氧化应激的第一道防线, 因为O2被转换成氧气与过氧化氢, 过氧化氢酶再将后者转换成水[82]。镉对这些酶的影响取决于暴露时间与剂量[83], 急性暴露耗尽实验动物体内的超氧化物歧酶和过氧化氢酶的活性[77]。镉与过氧化氢酶1个位点、超氧化物歧酶2个位点相结合, 导致酶二级结构改变与酶错误折叠, 从而丧失活性[84]。急性镉暴露降低谷胱甘肽过氧化物酶活性, 可能由于谷胱甘肽过氧化物酶与金属硫蛋白竞争含硫氨基酸。慢性镉暴露增加肾中抗氧化酶活性[85-87], 长期低剂量镉暴露可能刺激细胞防御机制, 例如激活核红2相关因子2 (nuclear erythroid 2-related factor 2, Nrf2), 并诱导金属硫蛋白的产生。由于铜、锌是超氧化物歧化酶的辅助因子, 提升两者水平有助于镉诱导超氧化物歧酶活性[83]

镉在血管组织中激活还原型辅酶Ⅱ氧化酶、黄嘌呤氧化酶以及一氧化氮合酶, 诱导氧化应激反应[88]。还原型辅酶Ⅰ/还原型辅酶Ⅱ氧化酶自还原型辅酶Ⅱ传递电子给氧分子而产生超氧阴离子, 其活性在高血压动物模型中增加[89-90]。黄嘌呤氧化酶来自氧化应激下的黄嘌呤脱氢酶[91], 内皮型一氧化氮合酶则是左旋精氨酸缺乏时超氧化物的来源。在正常情况下, 一氧化氮合酶将左旋精氨酸氧化成左旋瓜精氨酸以产生一氧化氮。当左旋精氨酸缺乏时, 一氧化氮合酶产生超氧化物, 超氧化物迅速与一氧化氮反应生成过氧亚硝基阴离子。这个效应称为一氧化氮合酶解偶联, 可能与心血管疾病有关[88]

3.2   镉诱导氧化应激的后果

镉引起氧化应激, 导致脂质过氧化, 伤害生物膜的完整与功能。丙二醛被用来监测脂质过氧化情形。DJUKIĆ-COSIĆ等[85]研究发现, 小鼠染镉后的丙二醛水平与肝脏铁含量呈正相关, 证实镉通过芬顿反应产生活性氧, 导致脂质过氧化。NEMMICHE等[92]对大鼠注射2 mg/kg氯化镉10 d后, 大鼠肝与脑中丙二醛明显增加; 令人惊讶的是, 脑中丙二醛增加50%, 肝中仅增加32%。AGNIHOTRI等[93]以0.1、0.5、1.0、2.0 mg/L氯化镉喂食瑞士白鼠, 发现镉在肾、肝、脾、睪丸以及脑中引起氧化应激且呈剂量反应关系; 鼠脑中蓄积的丙二醛最多, 显示脑对镉所致氧化应激的抵抗最为脆弱。

氧化应激在急性镉中毒中扮演重要的角色, 对慢性中毒的意义则尚不明确[94]。机体对慢性镉暴露逐渐适应后, 活性氧的产生减少, 但DNA氧化损伤的细胞在分裂增殖过程可能引起肿瘤[94]。Nrf2是细胞抗氧化反应的重要调节器, 活性氧能激活Nrf2 [95]。研究[96]表明, 斑马鱼在注射镉金属后, 通过Nrf2、NF-κB的转录调控在脑、肝、卵巢引起氧化应激与炎症反应。大鼠的小胶质细胞染镉后, NF-κB与激活蛋白-1皆明显增加[97]。此外, 镉暴露能促进NF-κB与DNA结合, 增加血红素加氧酶-1、金属硫蛋白-1、金属转运蛋白-1以及谷胱甘肽硫转移酶pi的表达。这些基因表达可视为对抗镉所致氧化应激的重要机制。相反, 也有研究[98]表明, 镉暴露降低大鼠肾表皮细胞中NF-κB与DNA的结合, 显示镉抑制NF-κB活性, 通过氧化应激引起细胞凋亡。Nrf2、NF-κB激活后与Keap1、I-κB分离, 移位到细胞核, 在核内调控抗氧化基因与抗炎症基因的转录。

3.3   镉引起的氧化应激、细胞凋亡与细胞坏死

研究表明低浓度镉能促发细胞凋亡, 高浓度镉则引起细胞坏死[99]。镉引起细胞凋亡的相关现象包括细胞收缩、膜联蛋白V过度表达、活性氧生成、DNA断裂以及细胞周期阻滞[100]。同一研究发现镉在西伯利亚虎成纤细胞中能抑制DNA合成, 降低线粒体膜电位, 破坏钙平衡, 激活半胱天冬酶-3、-8、-9, 引起细胞凋亡, 相似结果也在小鼠皮肤成纤细胞实验中出现[100]。其他研究[98]同样表明, 镉能激活半胱天冬酶-3、-7、-9, 并造成DNA断裂。

4   镉与遗传毒性

细菌与哺乳类动物细胞研究显示, 镉干扰DNA修复过程, 间接发挥致突变效应[101]。在大肠杆菌实验中, 镉使O6–甲基鸟嘌呤-DNA甲基转移酶发生钝化, 而与甲基亚硝基脲联合发挥致突变效应[102-103]。当哺乳类动物细胞暴露于紫外线时, 镉能提高突变频率, 抑制DNA合成, 引起DNA断裂与染色体畸变的积累[104]。研究[105-106]显示, 高浓度镉能使DNA聚合酶失活, 抑制人成纤维细胞DNA的修复。此外, 镉使人喉癌细胞的DNA双链断裂, 且呈剂量反应关系[107], 表明镉可能是头颈癌的原因之一。通过实时荧光定量PCR与随机扩增多态性DNA技术, CAMBIER等[108]的研究结果表明, 镉在一般环境剂量下便能引起遗传毒性。在啮齿类动物身上主要利用微核试验、彗星试验与8-羰基鸟苷来进行遗传毒性研究。对瑞士白鼠注射5 mg/kg氯化镉后, 骨髓细胞染色体畸变增加, 使用抗氧化剂前处理白鼠7 d, 则镉的致突变效应明显降低[109]。当小鼠慢性染毒后, 镉在上下消化道发挥遗传毒性效应, 但作者并未在肠道观察到氧化应激相关基因变化, 因此推论镉的遗传毒性与氧化应激无关[110]。另一项研究[111]表明, 镉在小鼠骨髓细胞引起DNA损伤, 且呈剂量反应关系。随着镉暴露量升高, 骨髓细胞中还原型谷胱甘肽水平下降, 脂质过氧化水平增加, 显示活性氧的生成促进了镉的遗传毒性。镉染毒Wistar大鼠的血液与肝细胞内微核和DNA断裂增加[112]。镉染毒肝细胞中8-羟基-2-脱氧鸟苷明显表达, 而8-羟基-2-脱氧鸟苷是重要的氧化应激与致癌作用生物指标, 反映早期线粒体DNA氧化损伤[113]。总结研究结果可以认为:镉的遗传毒性存在两个分子机制, 第一个机制是干扰DNA修复过程, 包括碱基切补修复、核苷酸切补修复和错配修补等, 第二个机制则与活性氧的产生有关[114]

镉对人类遗传毒性的研究结果并不一致。HENGSTLER等[115]利用碱性洗脱方法测量DNA单链断裂, 发现DNA断裂与工人作业场所空气中镉浓度相关。高镉暴露能诱导微核的产生, 在5个细胞因子阻滞微核试验研究中, 只有2个显示镉具有遗传毒性[116], 这可能是由于镉的剂量不同。镉的致癌分子机制包括基因表达与信号转导失调、氧化应激、钙黏着蛋白断裂、抑制DNA修复、干扰细胞凋亡等[81]。镉在微摩尔浓度水平即能上调动物细胞中的c-fosc-junc-myc基因。对小鼠注射氯化镉能诱导c-jun基因, 且呈剂量反应关系[117]。镉在动物细胞中诱导应激反应蛋白基因与金属硫蛋白合成基因的表达, 大、小鼠研究皆显示, 当金属硫蛋白减少时镉的致癌作用增加。镉影响谷胱甘肽合成基因的表达, 并使热休克基因过度表达[81]。科学家提出若干镉诱导基因失调的机制, 其中最重要的是有关第二信使增加的机制, 例如活性氧与钙(Ⅱ)转录因子[81]。此外, 镉中毒产生活性氧, 诱导AP-1转录激活, 导致c-fosc-jun原癌基因的过度表达[118]。此外, 若干研究探讨了镉与金属反应转录因子1的关系, 当金属反应转录因子1受抑制时可以消除镉所导致的金属硫蛋白的过度表达[119-120]

5   镉对靶器官的毒作用

镉能引起近端肾小管伤害, 增加尿中生物指标, 导致范可尼综合征, 甚至慢性肾衰竭[121]。肾毒性的分子机制包括氧化应激、线粒体功能受损以及细胞凋亡[122]等。镉的肺毒性主要通过吸入途径发生, 血镉浓度与肺功能损伤有关[123]。肺毒性的分子机制包括氧化应激、促炎症细胞因子增加与细胞凋亡[124]。骨质疏松是慢性镉中毒的重要表现, 导致骨折风险升高, 且呈剂量反应关系[125]。骨毒性的机制可能与c-fos基因有关, 导致骨质吸收[126]。美国疾病预防控制中心国家健康和营养调查调查结果显示, 血镉和尿镉与心血管疾病风险、心脏病以及冠状动脉心脏病死亡率有关[127]。此毒性机制以血管内皮为靶目标, 包括调节黏附分子, 影响一氧化氮生成, 破坏MAPK、ERK和NK信号通路[128], 导致细胞凋亡与细胞坏死。此外, 长期镉暴露可能引起前列腺癌、肺癌、乳腺癌与卵巢癌。

6   结论

目前的研究结果表明, 镉通过毒性机制在各器官系统引起不良健康效应(图 1), 例如降低抗氧化系统活性(超氧化物歧酶、过氧化氢酶、谷胱甘肽), 拮抗锌的功能, 增加活性氧的生成以及促进氧化应激。过多活性氧能产生过氧亚硝基阴离子, 限制一氧化氮的可利用性, 导致依赖一氧化氮的生理功能受到削弱, 包括氧化还原信号与血管收缩。氧化应激所致氧化还原失衡与促炎转录因子的激活互相关联, 导致促炎细胞因子过度产生与过度的炎症反应。镉抑制DNA修复机制, 扩大DNA氧化损伤, 改变基因表达, 增加基因突变, 从而介导镉的致癌作用。此外, 镉诱导DNA损伤、氧化应激以及转录因子调控, 导致细胞凋亡和细胞坏死。了解和控制镉的毒作用机制对于预防镉中毒、维持和改善人类身体健康具有重要意义。

图 1

镉的毒性机制

表1

镉的理化特性

Table 1
图 1

镉的毒性机制

Figure 1

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[作者简介] Alexey A.TINKOV (1989-), 男, 博士, 主治医师; 研究方向:环境毒理学 tinkov.a.a@gmail.com

[收稿日期] 2017-08-16 00:00:00.0

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