付騰騰，黃厚今

(遵義醫(yī)學院 公共衛(wèi)生學院， 貴州 遵義 563099)

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綜 述

鎘的雄性生殖毒性及其拮抗藥物的研究進展

付騰騰，黃厚今

(遵義醫(yī)學院 公共衛(wèi)生學院， 貴州 遵義 563099)

鎘(Cadmium， Cd)是一種主要的工業(yè)和環(huán)境污染物，可造成多種器官的急慢性病理損傷。雄性生殖系統(tǒng)對鎘尤為敏感。本文綜述鎘對雄性生殖系統(tǒng)的毒性，及其拮抗的研究進展。

鎘；雄性生殖毒性；睪丸；拮抗藥物

鎘(Cd)是一種毒性極強的工業(yè)和環(huán)境污染物，主要來自采礦、冶煉、電鍍、電池、顏料、塑料等工業(yè)生產的廢料及香煙煙霧和農業(yè)肥料。鎘可能造成急慢性病理損傷，如肝腎功能異常，睪丸損傷等。人體很容易從受污染的食物、水和空氣中攝取鎘，每人每天平均通過胃腸道從食物和水中攝取約30 μg鎘，抽煙者每日通過肺從每包香煙中額外吸收1-3 μg的鎘，進入體內的鎘經代謝轉運蓄積在腎臟、肝等器官中。鎘在人體內的半衰期很長，為20～30年；而排泄率很低，每天小于1～2 μg。睪丸是鎘的主要靶器官之一，且睪丸對鎘的毒性及其敏感，低劑量(1～2 mg/kg bwt)的鎘會即會引起睪丸組織學損傷而對其他器官并無組織學影響[1]。研究發(fā)現(xiàn)，無精癥患者與少精患者相比，血漿和睪丸勻漿中有更多的鎘[2]，而且大鼠的鎘接觸和弱精子癥之間呈正相關關系[3]。因此，對鎘造成的生

殖毒性以及拮抗藥物的研究具有重要意義。

1 鎘對雄性生殖系統(tǒng)的毒性

根據以往的研究，鎘對雄性生殖系統(tǒng)的損傷包括組織和器官的嚴重出血、水腫和萎縮，以及精原細胞凋亡，精子數(shù)量上的減少和動力、活力的降低，睪酮(testosterone，T)在血漿和睪丸中的濃度降低；體外實驗顯示，鎘能夠刺激間質細胞凋亡，破壞血睪屏障[4-5]。

血睪屏障(blood-testis barrier，BTB)是由支持細胞為主體構成的保護屏障；它為減數(shù)分裂細胞和準備減數(shù)分裂細胞提供一個免疫保護和可控的生化環(huán)境[6-9]。血睪屏障是由緊密連接(tight junction，TJ)、間隙連接、細胞外質特化區(qū)和橋粒連接組成的[10-12]。鎘能損傷BTB生殖細胞緊密連接[13]，從而導致生殖細胞減少、精子數(shù)量減少、雄性生殖能力低下甚至不育。

1.1 鎘對雄性大鼠性腺的毒性作用 鎘對體重的影響存在不一致的結果，很多實驗顯示鎘對體重無影響[14-15]，但也有部分實驗發(fā)現(xiàn)鎘可顯著降低大鼠的體重[16-18]。

在Predes等[19]的實驗中，性腺指數(shù)(GSI，gonadosomatic index，GSI=100×睪丸重量/大鼠體重)在鎘處理后有明顯下降，生精小管長度也明顯降低。在Zhou等[20]的實驗中，大鼠的睪丸、附睪以及精囊的臟器系數(shù)均因染鎘明顯下降，精子發(fā)生也明顯減少。然而一些作者也觀察到精囊和前列腺重量沒有變化[21-22]。

1.3 睪酮(T)水平 在Liu等[23]的實驗中，睪丸睪酮水平在鎘暴露后顯著降低。在ADEL[24]的實驗中，血清睪酮水平在鎘暴露后顯著降低。

1.4 鎘對生殖細胞的影響

1.4.1 對精子數(shù)量、活動度和形態(tài)的影響 鎘能夠降低精子數(shù)量、每日精子產量[25]和降低精子運動能力，顯著升高精子畸形率，從而影響雄性生育能力。鎘的毒性可能導致多核巨細胞的形成。這種多核巨細胞形成是由于初級精母細胞的減數(shù)分裂，卻沒有額外復制DNA[26]。

1.4.2 生殖細胞凋亡 與對照組相比，鎘處理組曲細精管中有更多的TUNEL陽性生殖細胞[23]，生精細胞Bax標記物的表達增加，Ki-67呈下降趨勢[24]；Bax和Ki-67分別是促凋亡和細胞增殖的標記。

鎘誘導的鈣離子超載以多種方式在多種細胞內誘導細胞凋亡。鎘可使Bcl-2降低和Bax的升高；Bcl-2抑制胞內鈣離子升高，Bax促進胞內鈣離子升高，從而觸發(fā)細胞凋亡[27]。鈣離子升高還可激活鈣蛋白酶，導致HEK293細胞的凋亡[28]。胞內鈣離子超載還能使線粒體膜電位(△Ψm)去極化從而誘導細胞凋亡[29]。

1.5 氧化狀態(tài)和抗氧化狀態(tài) 丙二醛(malondialdehyde，MDA)是過氧化脂質的終產物，并且是活性氧簇(reactive oxygen species，ROS)誘導的氧化應激的指示劑。與對照組相比，鎘處理組過氧化脂(lipid peroxides，LPO)的產生顯著升高，睪丸[23]和血清[24]MDA活性均顯著增加。

抗氧化酶主要包括超氧化物歧化酶(superoxide dismutase，SOD)、過氧化氫酶(catalase，CAT)、谷胱甘肽過氧化物酶(glutathione peroxidase，GSH-Px)等。與對照組相比，鎘暴露組SOD活性下降約50%，也顯著抑制谷胱甘肽(glutathione，GSH)和CAT在睪丸組織勻漿中的活性[23]。從而導致過氧化氫的積累，進而引起睪丸間質細胞激素合成受到抑制[30]。

因鎘無法像其他金屬離子一樣直接接收及傳遞電子，故鎘極少通過芬頓反應(Fenton-type)參與自由基形成，鎘主要通過抑制自由基清除酶活性而增強ROS對細胞的損傷[31]。鎘誘導的氧化應激主要有三種機制：一是消耗抗氧化酶[32]如谷胱甘肽還原酶；二是與各種蛋白質(如細胞膜蛋白、胞質蛋白和酶)上的巰基反應；三是通過損傷線粒體，加強活性氧的生產[33-34]。

腦癱是小兒常見的神經系統(tǒng)疾病，是指患兒出生后1個月內因非進行性腦受損所致，臨床表現(xiàn)存在多樣性，現(xiàn)如今小兒腦癱發(fā)病率呈明顯上升趨勢，隨著醫(yī)學技術的不斷進步，其存活率已得到改善[8-9]。手術為癥狀嚴重者的主要治療手段，能夠有效改善患兒功能，多于全麻下進行，七氟醚為小兒麻醉的誘導藥物，其起效快速，對氣道刺激較小，能夠促進氣道平滑肌松弛，對肌松藥的強化作用明顯優(yōu)于恩氟醚及異氟醚[10]。但存在惡心嘔吐、咽部不適等不足，加之手術疼痛能夠引起蘇醒期躁動，導致患兒煩躁不安。既往多予以氯胺酮或者阿片類藥物鎮(zhèn)痛以預防躁動，但其可能導致呼吸抑制，影響患兒清醒質量[11]。

鎘在三肽減少的GSH中與巰基結合形成復合物，而GSH是細胞內主要的抗氧化物質。因為它可以防止重金屬造成進一步的破壞，在某些情況下通過特定的轉運蛋白的清除Cd2+，故GSH與Cd2+結合是防御的第一道防線[35-37]。

鎘會增加促凋亡基因p53和Bax的表達，降低抗凋亡基因Bcl-2的表達[38-39]，通過特定的信號轉導通路和信號分子在破壞血睪屏障，如p38絲裂原活化蛋白激酶[27]。

線粒體是鎘致毒性的中心靶點。鎘可能通過線粒體通透性轉換孔(mitochondrial permeablity transition pore，mPTP)[40]、線粒體鈣單向轉運體(mitochondrial calcium uniporter，MCU)[41]等途徑進入線粒體中。染鎘后導致的睪丸損傷和精子毒性的發(fā)病機制已被證明與氧化損傷有關，即線粒體損傷導致活性氧簇(ROS)形成。同時，線粒體是細胞內重要的鈣離子倉庫，鎘會導致鈣轉運和平衡的競爭性抑制。ROS和Ca2+的混亂導致線粒體狀態(tài)發(fā)生大量的變化，包括氧化磷酸化作用的降低，線粒體膜電位去極化，過氧化物增加和ATP產生減少[42]，最終導致線粒體自噬[43-44]。

2 拮抗鎘毒性藥物的作用機制

2.1 抗氧化機制 鎘本身并不直接產生自由基，而是通過多方面的機制(包括減弱抗氧化防御和損傷線粒體產生ROS)誘導氧化應激。

許多化合物或植物具有“抗氧化”的功能，但實際上是通過上調Nrf2信號從而強化抗氧化機制[45]。短期可能使生成的ROS改善，長期可能會造成致癌作用[46]。

2.2 保護線粒體 鎘不僅增加ROS水平從而損傷線粒體，而且由于線粒體儲存Ca2+，鎘破壞了線粒體內鈣離子的動態(tài)平衡最終導致線粒體自噬，故保護線粒體的方法仍是抗氧化干預。

丙酮酸能減少氧化應激；而褪黑素能直接保護線粒體[42]；細胞自身也有各種方式保護線粒體，線粒體代謝的調控是拮抗鎘損害線粒體的關鍵措施，但也有抗凋亡信號的風險。

2.3 金屬螯合 與鎘結合的螯合劑是保護細胞免受損傷的一種主要解毒的機制。金屬硫蛋白(metallothionein，MT)是一種重要的鎘結合蛋白，其主要職責就是平衡體內金屬和解毒作用[47]，MTs主要在肝臟中表達。谷胱甘肽是一種抗氧化劑，也是一種能結合鎘金屬螯合劑。最近發(fā)現(xiàn)的由谷胱甘肽分子縮合而成植物螯合肽(phytochelatin，PC)，也可作為結合鎘的解毒劑，并且與MTs的貯存和排泄鎘的方式(溶酶體)不同[48-49]。

鎘與螯合劑螯合是相當有效的解毒方式，然而金屬結合蛋白降解則會導致鎘的再次釋放。

2.4 拮抗大分子損傷 細胞內的鈣離子主要儲存在內質網(endoplasmic reticulum，ER)，ER是蛋白質折疊和復位的場所，鎘通過改變鈣離子穩(wěn)態(tài)，導致ER應激[50]。

未折疊蛋白反應(unfolded protein response，UPR)的上調是ER應激的一個標志，這個反應可激活促生存信號或誘導細胞凋亡。蛋白陪伴分子(如Grp78)的表達可降低大分子損傷引起內質網應激和隨后的UPR，Grp78存在于內質網中，可防止鎘誘導的蛋白折疊和復位[51-52]。熱激蛋白(heat shoct proteins，HSPs)作為蛋白陪伴分子參與蛋白折疊和抗氧化反應，HSPs能通過清除ROS拮抗鎘毒性[53]。

拮抗大分子損傷的機制是恢復或重建離子的動態(tài)平衡，重點在于抑制ER應激，但長期可能有致癌可能[46]。

2.5 減少鎘的攝入 鎘通過蛋白的主動或被動運輸進入細胞，其常用的吸收途徑為鈣、鐵、鋅等二價金屬離子的途徑，故下調金屬轉運蛋白可長期拮抗鎘等重金屬[54]。

3 防治鎘所致生殖系統(tǒng)障礙的藥物

近年來的實驗表明，α-生育酚、β-隱黃質、百里醌、茶黃素、瓜拉納籽粉、果膠、姜黃素、咖啡酸乙酯、木菠蘿提取物[55-60]、葡萄籽提取物[24]、辛伐他汀、銀杏葉提取物[15]、藏紅花提取物等均具有顯著的抗氧化作用，它們能夠明顯改善鎘引起的精子濃度、運動和畸形率變化，恢復血清睪酮水平，使SOD、CAT和GSH-Px上升，降低MDA，減少生殖細胞和間質細胞凋亡，有效拮抗鎘引起的生殖毒性。其中一些具有抗炎作用的藥物如百里醌、辛伐他汀[61-62]等，還能抑制一些腫瘤壞死因子、致炎性細胞因子等的產生。

除以上抗氧化物以外，白藜蘆醇對鎘誘導的睪丸損傷、激素水平和精液參數(shù)的干擾均有治療和保護作用[63]；二烯丙基硫化物顯著降低鎘和脂質過氧化指標的積累，顯著提高睪丸抗氧化防御系統(tǒng)的活動；燈籠果酸漿提取物顯著降低睪丸中的鎘，顯著改善鎘引起的睪丸質量下降，GSH、SOD、CAT、GSH-Px的降低，對鎘致大鼠睪丸氧化應激和細胞凋亡具有保護作用；海棗花粉提取物使染鎘組性腺的臟器系數(shù)幾乎接近對照組，顯著改善了精子參數(shù)和組織病理學檢查，也顯著改善了睪丸GSH下降，LPO和MDA上升；低劑量的鋰可以減少睪丸的腫瘤壞死因子α(tumor necrosis factor α，TNF-α和Bax以及血清的MDA，增加白細胞介素-4(IL-4)、Zn-Cu、SOD、Bcl-2水平，從而抑制鎘誘導的睪丸損傷；靈芝孢子粉能顯著提高鎘引起的雄激素結合蛋白(androgen-binding protein，ABP)、抑制素B(inhibin-B，INH-B)基因表達水平和血清T濃度水平降低，保護支持細胞，從而拮抗鎘造成的睪丸損傷；羅勒葉提取物能改善鎘導致的睪丸組織病變，升高Ki-67的表達；葡萄汁濃縮物可抑制鎘導致的組織形態(tài)學變化，能夠通過各種機制減輕長期鎘誘導的生殖損傷，并且具有劑量依賴性；生姜能顯著升高鎘導致的睪丸臟器系數(shù)降低，改善MDA增加；主要成分為中藥成分的生精膠囊提取物能增加精子數(shù)量，提高精子活力，改善鎘引起的大鼠血清睪酮降低，提高精子DNA碎片率以及睪丸和附睪MDA含量，提高抗氧化酶活性，修復睪丸和附睪病理性損傷，保護精子發(fā)生；左旋肉堿可能通過控制熱激蛋白70，從而有效改善鎘誘導的DNA損傷[64-69]。

除單一藥物作用外，也有一些藥物如抗壞血酸和鋅[70]、硫辛酸和硒、鋅和硒聯(lián)合作用，能起到比兩種藥物獨自作用更佳的效果。

4 結語

鎘是一種對人類有害的毒物。但是在工業(yè)和科技現(xiàn)階段仍會有這種副產物的產生，現(xiàn)階段仍然有必要探索預防和治療鎘損傷的有效藥物和方法。由于雄性生殖系統(tǒng)是對鎘最為敏感的部分之一，鎘對雄性生殖系統(tǒng)作用相關研究仍將是人們關注的焦點之一。

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[收稿2017-03-11;修回2017-05-14]

(編輯：譚秀榮)

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

貴州省科技廳聯(lián)合基金重點科研項目(NO:黔科合J字LMZ〔2013〕05)。

黃厚今，男，博士后，教授，碩士生導師，研究方向：營養(yǎng)毒理學，E-mail:Huanghj6688@163.com。

R114

A

1000-2715(2017)03-0333-06