镉的雄性生殖毒性及其拮抗药物的研究进展

付腾腾，黄厚今

(遵义医学院 公共卫生学院， 贵州 遵义 563099)



综 述

镉的雄性生殖毒性及其拮抗药物的研究进展

付腾腾，黄厚今

(遵义医学院 公共卫生学院， 贵州 遵义 563099)

镉(Cadmium， Cd)是一种主要的工业和环境污染物，可造成多种器官的急慢性病理损伤。雄性生殖系统对镉尤为敏感。本文综述镉对雄性生殖系统的毒性，及其拮抗的研究进展。

镉；雄性生殖毒性；睾丸；拮抗药物

镉(Cd)是一种毒性极强的工业和环境污染物，主要来自采矿、冶炼、电镀、电池、颜料、塑料等工业生产的废料及香烟烟雾和农业肥料。镉可能造成急慢性病理损伤，如肝肾功能异常，睾丸损伤等。人体很容易从受污染的食物、水和空气中摄取镉，每人每天平均通过胃肠道从食物和水中摄取约30 μg镉，抽烟者每日通过肺从每包香烟中额外吸收1-3 μg的镉，进入体内的镉经代谢转运蓄积在肾脏、肝等器官中。镉在人体内的半衰期很长，为20～30年；而排泄率很低，每天小于1～2 μg。睾丸是镉的主要靶器官之一，且睾丸对镉的毒性及其敏感，低剂量(1～2 mg/kg bwt)的镉会即会引起睾丸组织学损伤而对其他器官并无组织学影响[1]。研究发现，无精症患者与少精患者相比，血浆和睾丸匀浆中有更多的镉[2]，而且大鼠的镉接触和弱精子症之间呈正相关关系[3]。因此，对镉造成的生

殖毒性以及拮抗药物的研究具有重要意义。

1 镉对雄性生殖系统的毒性

根据以往的研究，镉对雄性生殖系统的损伤包括组织和器官的严重出血、水肿和萎缩，以及精原细胞凋亡，精子数量上的减少和动力、活力的降低，睾酮(testosterone，T)在血浆和睾丸中的浓度降低；体外实验显示，镉能够刺激间质细胞凋亡，破坏血睾屏障[4-5]。

血睾屏障(blood-testis barrier，BTB)是由支持细胞为主体构成的保护屏障；它为减数分裂细胞和准备减数分裂细胞提供一个免疫保护和可控的生化环境[6-9]。血睾屏障是由紧密连接(tight junction，TJ)、间隙连接、细胞外质特化区和桥粒连接组成的[10-12]。镉能损伤BTB生殖细胞紧密连接[13]，从而导致生殖细胞减少、精子数量减少、雄性生殖能力低下甚至不育。

1.1 镉对雄性大鼠性腺的毒性作用 镉对体重的影响存在不一致的结果，很多实验显示镉对体重无影响[14-15]，但也有部分实验发现镉可显著降低大鼠的体重[16-18]。

在Predes等[19]的实验中，性腺指数(GSI，gonadosomatic index，GSI=100×睾丸重量/大鼠体重)在镉处理后有明显下降，生精小管长度也明显降低。在Zhou等[20]的实验中，大鼠的睾丸、附睾以及精囊的脏器系数均因染镉明显下降，精子发生也明显减少。然而一些作者也观察到精囊和前列腺重量没有变化[21-22]。

1.3 睾酮(T)水平 在Liu等[23]的实验中，睾丸睾酮水平在镉暴露后显著降低。在ADEL[24]的实验中，血清睾酮水平在镉暴露后显著降低。

1.4 镉对生殖细胞的影响

1.4.1 对精子数量、活动度和形态的影响 镉能够降低精子数量、每日精子产量[25]和降低精子运动能力，显著升高精子畸形率，从而影响雄性生育能力。镉的毒性可能导致多核巨细胞的形成。这种多核巨细胞形成是由于初级精母细胞的减数分裂，却没有额外复制DNA[26]。

1.4.2 生殖细胞凋亡 与对照组相比，镉处理组曲细精管中有更多的TUNEL阳性生殖细胞[23]，生精细胞Bax标记物的表达增加，Ki-67呈下降趋势[24]；Bax和Ki-67分别是促凋亡和细胞增殖的标记。

镉诱导的钙离子超载以多种方式在多种细胞内诱导细胞凋亡。镉可使Bcl-2降低和Bax的升高；Bcl-2抑制胞内钙离子升高，Bax促进胞内钙离子升高，从而触发细胞凋亡[27]。钙离子升高还可激活钙蛋白酶，导致HEK293细胞的凋亡[28]。胞内钙离子超载还能使线粒体膜电位(△Ψm)去极化从而诱导细胞凋亡[29]。

1.5 氧化状态和抗氧化状态 丙二醛(malondialdehyde，MDA)是过氧化脂质的终产物，并且是活性氧簇(reactive oxygen species，ROS)诱导的氧化应激的指示剂。与对照组相比，镉处理组过氧化脂(lipid peroxides，LPO)的产生显著升高，睾丸[23]和血清[24]MDA活性均显著增加。

抗氧化酶主要包括超氧化物歧化酶(superoxide dismutase，SOD)、过氧化氢酶(catalase，CAT)、谷胱甘肽过氧化物酶(glutathione peroxidase，GSH-Px)等。与对照组相比，镉暴露组SOD活性下降约50%，也显著抑制谷胱甘肽(glutathione，GSH)和CAT在睾丸组织匀浆中的活性[23]。从而导致过氧化氢的积累，进而引起睾丸间质细胞激素合成受到抑制[30]。

因镉无法像其他金属离子一样直接接收及传递电子，故镉极少通过芬顿反应(Fenton-type)参与自由基形成，镉主要通过抑制自由基清除酶活性而增强ROS对细胞的损伤[31]。镉诱导的氧化应激主要有三种机制：一是消耗抗氧化酶[32]如谷胱甘肽还原酶；二是与各种蛋白质(如细胞膜蛋白、胞质蛋白和酶)上的巯基反应；三是通过损伤线粒体，加强活性氧的生产[33-34]。

脑瘫是小儿常见的神经系统疾病，是指患儿出生后1个月内因非进行性脑受损所致，临床表现存在多样性，现如今小儿脑瘫发病率呈明显上升趋势，随着医学技术的不断进步，其存活率已得到改善[8-9]。手术为症状严重者的主要治疗手段，能够有效改善患儿功能，多于全麻下进行，七氟醚为小儿麻醉的诱导药物，其起效快速，对气道刺激较小，能够促进气道平滑肌松弛，对肌松药的强化作用明显优于恩氟醚及异氟醚[10]。但存在恶心呕吐、咽部不适等不足，加之手术疼痛能够引起苏醒期躁动，导致患儿烦躁不安。既往多予以氯胺酮或者阿片类药物镇痛以预防躁动，但其可能导致呼吸抑制，影响患儿清醒质量[11]。

镉在三肽减少的GSH中与巯基结合形成复合物，而GSH是细胞内主要的抗氧化物质。因为它可以防止重金属造成进一步的破坏，在某些情况下通过特定的转运蛋白的清除Cd2+，故GSH与Cd2+结合是防御的第一道防线[35-37]。

镉会增加促凋亡基因p53和Bax的表达，降低抗凋亡基因Bcl-2的表达[38-39]，通过特定的信号转导通路和信号分子在破坏血睾屏障，如p38丝裂原活化蛋白激酶[27]。

线粒体是镉致毒性的中心靶点。镉可能通过线粒体通透性转换孔(mitochondrial permeablity transition pore，mPTP)[40]、线粒体钙单向转运体(mitochondrial calcium uniporter，MCU)[41]等途径进入线粒体中。染镉后导致的睾丸损伤和精子毒性的发病机制已被证明与氧化损伤有关，即线粒体损伤导致活性氧簇(ROS)形成。同时，线粒体是细胞内重要的钙离子仓库，镉会导致钙转运和平衡的竞争性抑制。ROS和Ca2+的混乱导致线粒体状态发生大量的变化，包括氧化磷酸化作用的降低，线粒体膜电位去极化，过氧化物增加和ATP产生减少[42]，最终导致线粒体自噬[43-44]。

2 拮抗镉毒性药物的作用机制

2.1 抗氧化机制 镉本身并不直接产生自由基，而是通过多方面的机制(包括减弱抗氧化防御和损伤线粒体产生ROS)诱导氧化应激。

许多化合物或植物具有“抗氧化”的功能，但实际上是通过上调Nrf2信号从而强化抗氧化机制[45]。短期可能使生成的ROS改善，长期可能会造成致癌作用[46]。

2.2 保护线粒体 镉不仅增加ROS水平从而损伤线粒体，而且由于线粒体储存Ca2+，镉破坏了线粒体内钙离子的动态平衡最终导致线粒体自噬，故保护线粒体的方法仍是抗氧化干预。

丙酮酸能减少氧化应激；而褪黑素能直接保护线粒体[42]；细胞自身也有各种方式保护线粒体，线粒体代谢的调控是拮抗镉损害线粒体的关键措施，但也有抗凋亡信号的风险。

2.3 金属螯合 与镉结合的螯合剂是保护细胞免受损伤的一种主要解毒的机制。金属硫蛋白(metallothionein，MT)是一种重要的镉结合蛋白，其主要职责就是平衡体内金属和解毒作用[47]，MTs主要在肝脏中表达。谷胱甘肽是一种抗氧化剂，也是一种能结合镉金属螯合剂。最近发现的由谷胱甘肽分子缩合而成植物螯合肽(phytochelatin，PC)，也可作为结合镉的解毒剂，并且与MTs的贮存和排泄镉的方式(溶酶体)不同[48-49]。

镉与螯合剂螯合是相当有效的解毒方式，然而金属结合蛋白降解则会导致镉的再次释放。

2.4 拮抗大分子损伤 细胞内的钙离子主要储存在内质网(endoplasmic reticulum，ER)，ER是蛋白质折叠和复位的场所，镉通过改变钙离子稳态，导致ER应激[50]。

未折叠蛋白反应(unfolded protein response，UPR)的上调是ER应激的一个标志，这个反应可激活促生存信号或诱导细胞凋亡。蛋白陪伴分子(如Grp78)的表达可降低大分子损伤引起内质网应激和随后的UPR，Grp78存在于内质网中，可防止镉诱导的蛋白折叠和复位[51-52]。热激蛋白(heat shoct proteins，HSPs)作为蛋白陪伴分子参与蛋白折叠和抗氧化反应，HSPs能通过清除ROS拮抗镉毒性[53]。

拮抗大分子损伤的机制是恢复或重建离子的动态平衡，重点在于抑制ER应激，但长期可能有致癌可能[46]。

2.5 减少镉的摄入 镉通过蛋白的主动或被动运输进入细胞，其常用的吸收途径为钙、铁、锌等二价金属离子的途径，故下调金属转运蛋白可长期拮抗镉等重金属[54]。

3 防治镉所致生殖系统障碍的药物

近年来的实验表明，α-生育酚、β-隐黄质、百里醌、茶黄素、瓜拉纳籽粉、果胶、姜黄素、咖啡酸乙酯、木菠萝提取物[55-60]、葡萄籽提取物[24]、辛伐他汀、银杏叶提取物[15]、藏红花提取物等均具有显著的抗氧化作用，它们能够明显改善镉引起的精子浓度、运动和畸形率变化，恢复血清睾酮水平，使SOD、CAT和GSH-Px上升，降低MDA，减少生殖细胞和间质细胞凋亡，有效拮抗镉引起的生殖毒性。其中一些具有抗炎作用的药物如百里醌、辛伐他汀[61-62]等，还能抑制一些肿瘤坏死因子、致炎性细胞因子等的产生。

除以上抗氧化物以外，白藜芦醇对镉诱导的睾丸损伤、激素水平和精液参数的干扰均有治疗和保护作用[63]；二烯丙基硫化物显著降低镉和脂质过氧化指标的积累，显著提高睾丸抗氧化防御系统的活动；灯笼果酸浆提取物显著降低睾丸中的镉，显著改善镉引起的睾丸质量下降，GSH、SOD、CAT、GSH-Px的降低，对镉致大鼠睾丸氧化应激和细胞凋亡具有保护作用；海枣花粉提取物使染镉组性腺的脏器系数几乎接近对照组，显著改善了精子参数和组织病理学检查，也显著改善了睾丸GSH下降，LPO和MDA上升；低剂量的锂可以减少睾丸的肿瘤坏死因子α(tumor necrosis factor α，TNF-α和Bax以及血清的MDA，增加白细胞介素-4(IL-4)、Zn-Cu、SOD、Bcl-2水平，从而抑制镉诱导的睾丸损伤；灵芝孢子粉能显著提高镉引起的雄激素结合蛋白(androgen-binding protein，ABP)、抑制素B(inhibin-B，INH-B)基因表达水平和血清T浓度水平降低，保护支持细胞，从而拮抗镉造成的睾丸损伤；罗勒叶提取物能改善镉导致的睾丸组织病变，升高Ki-67的表达；葡萄汁浓缩物可抑制镉导致的组织形态学变化，能够通过各种机制减轻长期镉诱导的生殖损伤，并且具有剂量依赖性；生姜能显著升高镉导致的睾丸脏器系数降低，改善MDA增加；主要成分为中药成分的生精胶囊提取物能增加精子数量，提高精子活力，改善镉引起的大鼠血清睾酮降低，提高精子DNA碎片率以及睾丸和附睾MDA含量，提高抗氧化酶活性，修复睾丸和附睾病理性损伤，保护精子发生；左旋肉碱可能通过控制热激蛋白70，从而有效改善镉诱导的DNA损伤[64-69]。

除单一药物作用外，也有一些药物如抗坏血酸和锌[70]、硫辛酸和硒、锌和硒联合作用，能起到比两种药物独自作用更佳的效果。

4 结语

镉是一种对人类有害的毒物。但是在工业和科技现阶段仍会有这种副产物的产生，现阶段仍然有必要探索预防和治疗镉损伤的有效药物和方法。由于雄性生殖系统是对镉最为敏感的部分之一，镉对雄性生殖系统作用相关研究仍将是人们关注的焦点之一。

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[收稿2017-03-11;修回2017-05-14]

(编辑：谭秀荣)

Research progress on cadmium: testicular toxicity and the prevention and treatment

FuTengteng,HuangHoujin

(Department of Public Health,Zunyi Medical University,Zunyi Guizhou,563099,China)

Cadmium,a major industrial and environmental pollutant,can cause acute and chronic pathological injury of multiple organs.Moreover,cadmium is toxic to reproductive system in male animals.This article reviews the mechanism of certain male reproductive system damage caused by cadmium,and pharmacological agents for cadmium prevention and treatment,and research progress of pharmaceuticals for cadmium-induced testicular dysfunction.

Cadmium; male reproductive system; testis; protective effect; pharmaceuticals

贵州省科技厅联合基金重点科研项目(NO:黔科合J字LMZ〔2013〕05)。

黄厚今，男，博士后，教授，硕士生导师，研究方向：营养毒理学，E-mail:Huanghj6688@163.com。

R114

A

1000-2715(2017)03-0333-06