吳楊洋,彭祥雯,史可欣,匡雯潔,孫 宏,黃 蕾*

Se-Ca聯(lián)合膳食干預(yù)緩解Cd誘導(dǎo)小鼠肝腎毒性

吳楊洋1,彭祥雯1,史可欣1,匡雯潔1,孫 宏2,黃 蕾1*

(1.南京大學(xué)環(huán)境學(xué)院,污染控制與資源化研究國(guó)家重點(diǎn)實(shí)驗(yàn)室, 江蘇 南京 210023；2.江蘇省疾病預(yù)防控制中心,江蘇 南京 210023)

為探究Se-Ca聯(lián)合膳食干預(yù)對(duì)生物Cd中毒的緩解效果,選取88只BALB/c 小鼠,隨機(jī)劃分為19組,在相同飼料Cd暴露濃度下(2mg/kg)分別設(shè)置低、中、高濃度的Se和Ca單獨(dú)和聯(lián)合膳食干預(yù)處理,并觀察30d后小鼠的生長(zhǎng)發(fā)育、肝腎功能、氧化應(yīng)激狀態(tài)和組織病理變化.結(jié)果顯示,Se-Ca聯(lián)合干預(yù)可有效緩解Cd蓄積所致小鼠生長(zhǎng)發(fā)育遲緩現(xiàn)象,且進(jìn)一步促進(jìn)小鼠生長(zhǎng);肝腎功能及氧化應(yīng)激指標(biāo)測(cè)定結(jié)果表明,Se-Ca聯(lián)合干預(yù)對(duì)Cd暴露下小鼠肝臟AST、GSH、SOD、GSH-Px和腎臟BUN、MDA、SOD的保護(hù)效果優(yōu)于單一元素干預(yù);聯(lián)合干預(yù)僅需較小劑量即可達(dá)到單獨(dú)Se或Ca干預(yù)對(duì)肝腎病理損傷的最佳緩解效果.Se-Ca聯(lián)合膳食干預(yù)可有效緩解Cd攝入導(dǎo)致的生長(zhǎng)發(fā)育緩慢和肝腎毒性,且較之單一元素的干預(yù)效果更佳.

鎘；膳食硒鈣補(bǔ)充；膳食干預(yù)；肝腎損傷

鎘(Cd)是當(dāng)下我國(guó)農(nóng)業(yè)土壤的主要重金屬污染物[1-2],它可通過膳食攝入蓄積于人體肝臟、腎臟,導(dǎo)致肝毒性、腎毒性[3].環(huán)境中存在的低劑量Cd同樣會(huì)引發(fā)人和動(dòng)物組織氧化損傷、誘發(fā)細(xì)胞凋亡,威脅臟器健康[4-6],并與人體心腦血管疾病[7]、腫瘤[8]等惡性疾病密切相關(guān).

已有研究通過添加礦物質(zhì)營(yíng)養(yǎng)元素緩解Cd致生物毒性[9-10].在Cd暴露條件下,小鼠分別攝入Se(0.1mg/kg體重)、Ca(2540～4710mg/kg體重)可顯著緩解Cd誘導(dǎo)的氧化應(yīng)激反應(yīng)及肝腎損傷[10],減少胃腸道中約50%的Cd吸收[9].硒(Se)作為人體必須微量元素和常量元素鈣(Ca)在生物體內(nèi)與Cd產(chǎn)生拮抗作用,抑制氧化應(yīng)激、降低Cd吸收效率,可有效減輕Cd對(duì)生物體的健康損害.

但此前研究?jī)H關(guān)注Se/Ca單獨(dú)干預(yù)的緩解效果,鮮有關(guān)注二者聯(lián)合干預(yù)降低Cd蓄積所致肝腎毒性的相關(guān)研究.本文通過小鼠動(dòng)物實(shí)驗(yàn)分別檢測(cè)多濃度梯度Se-Ca聯(lián)合膳食干預(yù)與單獨(dú)Se/Ca干預(yù)對(duì)相同Cd暴露環(huán)境下小鼠生長(zhǎng)發(fā)育、肝腎功能和氧化應(yīng)激的干預(yù)效果并進(jìn)行組織病理學(xué)觀察,旨在評(píng)估Se-Ca聯(lián)合飲食干預(yù)的有效性及最佳干預(yù)方案,為多元素膳食干預(yù)緩解Cd的生理毒性研究提供新思路.

1 材料與方法

1.1 實(shí)驗(yàn)動(dòng)物

SPF級(jí)6周齡健康Balb/C小鼠購(gòu)自青龍山實(shí)驗(yàn)動(dòng)物養(yǎng)殖場(chǎng)(中國(guó)南京).在標(biāo)準(zhǔn)動(dòng)物房條件下(12:12h光照/黑暗循環(huán),25℃和50%濕度)適應(yīng)性飼養(yǎng)一周,隨后進(jìn)行實(shí)驗(yàn).

1.2 實(shí)驗(yàn)分組與處理方案

表1 實(shí)驗(yàn)分組及處理方案

注: ♂代表雄性小鼠,♀代表雄性小鼠.

將88只雌雄各半小鼠隨機(jī)分為19組,平均體重 [SD] (17.2 ± 2.0)g.綜合考慮預(yù)實(shí)驗(yàn)結(jié)果及《食品安全國(guó)家標(biāo)準(zhǔn)食品中污染物限量》[11][GB2762-2017],確定小鼠攝入Cd水平為2mg/kg飼料.預(yù)實(shí)驗(yàn)結(jié)果表明,該劑量會(huì)導(dǎo)致小鼠30d內(nèi)產(chǎn)生肝臟及腎臟毒性.考慮小鼠飼料的適口性及相關(guān)標(biāo)準(zhǔn)[12],Se、Ca分別設(shè)置低、中、高濃度梯度的膳食干預(yù):Se(0.1,1, 10mg/kg飼料),Ca(2,20,100g/kg飼料).共計(jì)設(shè)置Ca單獨(dú)干預(yù) (3組)、Se單獨(dú)干預(yù)(3組)和Se-Ca聯(lián)合干預(yù)(9組) 3種干預(yù)方案,以探究Ca、Se單獨(dú)及聯(lián)合干預(yù)最佳劑量組合,具體實(shí)驗(yàn)分組及處理方案如表1所示.Cd、Ca和Se分別以CdCl2(分析純)、CaCO3(分析純)和硒代蛋氨酸(C5H11NO2Se)的形式添加到特制的鼠飼料中.以上試劑分別購(gòu)于南京晚晴化玻儀器有限公司和博美生物科技有限責(zé)任公司.

30d干預(yù)期內(nèi),早上9:00喂食小鼠約4g特制飼料并記錄小鼠體重,實(shí)驗(yàn)過程中沒有小鼠死亡.干預(yù)結(jié)束后,禁食12h,頸椎脫臼法處死小鼠.

1.3 樣品制備

頸椎脫臼法處死小鼠,眼眶取血,血液常溫靜置2h,3500r/min離心30min,收集血清保存于-80℃恒溫冰箱.迅速分離小鼠肝臟和腎臟,臟器左部固定于4%多聚甲醛(POM,南京森貝伽生物)溶液,制備常規(guī)病理組織石蠟切片用于組織病理學(xué)觀察;臟器右部分按1:9重量(g)/體積(mL)加入生理鹽水,并置于冰水浴中,漩渦混勻器混勻制得組織勻漿,2500r/min離心10min,取上清液,-20℃保存以檢測(cè)臟器功能和氧化應(yīng)激指標(biāo).

1.4 測(cè)定指標(biāo)與方法

1.4.1 臟器功能指標(biāo)檢測(cè) 分別使用谷丙轉(zhuǎn)氨酶試劑盒(C009-2-1)、谷草轉(zhuǎn)氨酶試劑盒(C010-1-1)測(cè)定血清谷丙轉(zhuǎn)氨酶(ALT)、谷草轉(zhuǎn)氨酶(AST)活性以表征肝臟功能.分別使用尿素氮試劑盒(C013- 2-1)、肌酐試劑盒(C011-1-1)測(cè)定血清尿素氮(BUN)、肌酐(Cr)含量.

1.4.2 氧化應(yīng)激相關(guān)指標(biāo)檢測(cè) 分別使用MDA檢測(cè)試劑盒(A003-1-2)、GSH檢測(cè)試劑盒(A006-1-1)、SOD檢測(cè)試劑盒(A001-3-2)、GSH-Px檢測(cè)試劑盒(A005-1-1)和CAT檢測(cè)試劑盒(A007-1-1)測(cè)定肝臟、腎臟丙二醛(MDA)和谷胱甘肽(GSH)含量,及超氧化物歧化酶(SOD)、谷胱甘肽過氧化物酶(GSH-Px)和過氧化氫酶(CAT)活性.以上試劑均購(gòu)于南京建成生物有限公司.

1.4.3 組織病理學(xué)觀察 肝臟、腎臟石蠟切片進(jìn)行蘇木素-伊紅(HE)染色.在光學(xué)顯微鏡下(200×)觀察組織病理學(xué)結(jié)構(gòu)變化并拍照,根據(jù)觀察結(jié)果,將小鼠臟器病變程度由輕到重分別記為0～4分(正常0分,輕微0.5分,輕度1分,中度2分,重度3分,非常嚴(yán)重4分).

1.5 統(tǒng)計(jì)學(xué)分析

實(shí)驗(yàn)數(shù)據(jù)以平均值±標(biāo)準(zhǔn)差(Mean ± SD)表示,依據(jù)表1組別編號(hào),進(jìn)行One-Way ANOVA、LSD事后檢驗(yàn)并進(jìn)行組間比較.數(shù)據(jù)統(tǒng)計(jì)分析基于SPSS 22.0軟件,并利用Origin 2018軟件作圖.當(dāng)<0.05時(shí)認(rèn)為具有統(tǒng)計(jì)學(xué)上的顯著性差異.

2 結(jié)果與分析

2.1 膳食干預(yù)對(duì)小鼠體重影響

由圖1可見, Ca、Se單獨(dú)及聯(lián)合干預(yù)均促進(jìn)小鼠體重增長(zhǎng),Cd暴露則起抑制作用.其中,Ca單獨(dú)干預(yù)對(duì)小鼠生長(zhǎng)發(fā)育的促進(jìn)作用呈劑量依賴關(guān)系,高Ca促進(jìn)小鼠體重增長(zhǎng)幅度最大(<0.001, (5.96±1.31)g). Se單獨(dú)干預(yù)、Se-Ca聯(lián)合干預(yù)未見劑量依賴關(guān)系.中Se干預(yù)下小鼠體重增量呈極顯著升高(<0.001),中Se低Ca組干預(yù)效果最佳(<0.001).對(duì)比單獨(dú)Ca、單獨(dú)Se和Se-Ca聯(lián)合干預(yù)中各組最佳劑量的干預(yù)效果表明,高Ca組對(duì)小鼠體重干預(yù)效果最佳,但3組之間未呈現(xiàn)統(tǒng)計(jì)學(xué)差異(>0.05).

圖1 各組小鼠體重變化比較

與對(duì)照組相比, *< 0.05, **< 0.01, ***< 0.001; 與Cd組相比,#< 0.05,##< 0.01,###< 0.001

2.2 小鼠肝腎功能檢測(cè)

肝(ALT、AST)、腎(BUN、Cr)功能指標(biāo)顯示,Cd組暴露引起肝、腎功能障礙,小鼠血清ALT和AST活性,以及BUN和Cr含量均極顯著高于對(duì)照組(<0.001).由圖2可見,Se、Ca單獨(dú)及聯(lián)合干預(yù)均可有效降低小鼠血清ALT和AST活性、BUN和Cr含量 (BUN<0.05,其他<0.001),高Se高Ca膳食干預(yù)對(duì)抑制Cd誘導(dǎo)ALT、AST和BUN升高現(xiàn)象的緩解作用最好,高Se干預(yù)對(duì)Cd誘導(dǎo)Cr升高的緩解效果最佳.

圖2 各組血清中ALT和AST活力及BUN和Cr含量結(jié)果

與對(duì)照組相比, *< 0.05, **< 0.01, ***< 0.001;與Cd組相比,#< 0.05,##< 0.01,###< 0.001

2.3 臟器氧化應(yīng)激指標(biāo)測(cè)定結(jié)果

圖3 各組小鼠肝臟SOD(a)、GSH-Px(b)和CAT(c)活性及MDA(d)和GSH(e)含量

與對(duì)照組相比, *< 0.05, **< 0.01, ***< 0.001; 與Cd組相比,#< 0.05,##< 0.01,###< 0.001

圖4 各組小鼠腎臟SOD(a)、GSH-Px(b)和CAT(c)的活性以及MDA(d)和GSH(e)的含量

與對(duì)照組相比, *< 0.05, **< 0.01, ***< 0.001; 與Cd組相比, #< 0.05,##< 0.01,###< 0.001

與對(duì)照組相比,Cd組小鼠肝臟及腎臟SOD、GSH-Px和CAT活性均顯著降低(SOD<0.01,其他<0.001),GSH含量顯著減少(<0.001),同時(shí)氧化應(yīng)激產(chǎn)物MDA含量顯著升高(<0.001)(圖3,圖4).肝腎氧化應(yīng)激指標(biāo)測(cè)定結(jié)果表明,Se、Ca單獨(dú)及聯(lián)合干預(yù)可有效緩解Cd誘發(fā)的氧化應(yīng)激反應(yīng),使之趨向于正常水平.肝臟氧化應(yīng)激指標(biāo)表明,高Se高Ca聯(lián)合干預(yù)對(duì)維持肝臟SOD、GSH-Px活性和GSH含量的保護(hù)作用最強(qiáng),高Se干預(yù)對(duì)MDA的抑制效果最強(qiáng),高Ca干預(yù)對(duì)Cd誘發(fā)的CAT活性降低現(xiàn)象緩解效果最好;對(duì)于腎臟,高Se高Ca組對(duì)提高SOD活性和抑制MDA含量的干預(yù)效果最強(qiáng),高Se干預(yù)可增強(qiáng)腎臟GSH和CAT活性,高Ca干預(yù)對(duì)GSH-Px保護(hù)效果最佳.

2.4 臟器病理損傷評(píng)估

如圖5所示, Cd組肝臟切片可見明顯的肝竇淤血和炎細(xì)胞浸潤(rùn)癥狀,而經(jīng)高Ca、高Se及中Se中Ca干預(yù)后的小鼠肝臟切片肝竇淤血明顯減少,且無炎細(xì)胞浸潤(rùn)癥狀,表明Se、Ca單獨(dú)及聯(lián)合干預(yù)均可部分緩解Cd引起的肝臟炎癥和病理損傷.如圖6所示, Cd組小鼠腎臟切片可見明顯的透明管型和炎細(xì)胞浸潤(rùn)癥狀.經(jīng)高Ca、高Se和中Se高Ca聯(lián)合干預(yù)后,小鼠腎臟切片透明管型和炎細(xì)胞浸潤(rùn)均減少,可見Se、Ca單獨(dú)及聯(lián)合干預(yù)同樣均可部分緩解Cd引起的腎臟炎癥和病理損傷.其中,高Ca組和高Se組腎臟切片炎細(xì)胞浸潤(rùn)癥狀完全消失.

圖5 各組小鼠肝臟病理切片

光學(xué)顯微鏡觀察(200′),黃色箭頭表示炎細(xì)胞浸潤(rùn),黑色箭頭表示肝竇淤血

圖6 各組小鼠腎臟病理切片

光學(xué)顯微鏡觀察(200′),黃色箭頭表示炎細(xì)胞浸潤(rùn),黑色箭頭表示透明管型

病理評(píng)估結(jié)果顯示(圖7),Cd組肝臟、腎臟病理評(píng)分均顯著高于對(duì)照組(<0.001).中Se中Ca劑量干預(yù)顯著降低小鼠肝臟病理評(píng)分(<0.01),對(duì)Cd誘導(dǎo)小鼠肝臟病理性損傷的緩解作用最好;中Se高Ca劑量干預(yù)顯著降低小鼠腎臟病理評(píng)分(<0.001),對(duì)Cd暴露下小鼠腎臟組織結(jié)構(gòu)的保護(hù)效果最佳.

圖7 各組小鼠肝臟和腎臟病理得分

與對(duì)照組相比, *< 0.05, **< 0.01, ***< 0.001; 與Cd組相比,#< 0.05,##< 0.01,###< 0.001

3 討論

Cd暴露顯著抑制小鼠體重增長(zhǎng),而不同濃度梯度Ca、Se單獨(dú)及聯(lián)合干預(yù)均促進(jìn)小鼠體重增長(zhǎng),故適量攝入Se、Ca有助于降低Cd對(duì)生物生長(zhǎng)發(fā)育的不利影響.其中,單獨(dú)干預(yù)效果與此前Su等[13]研究結(jié)果一致,食用富硒大米+Cd的小鼠60d后體重顯著高于Cd組,且高于對(duì)照組.不同干預(yù)下小鼠體重并未呈現(xiàn)顯著差異,Se-Ca聯(lián)合干預(yù)在促進(jìn)小鼠生長(zhǎng)方面并未優(yōu)于單一元素干預(yù).血液中ALT、AST與血清中BUN和Cr水平分別是臨床診斷中評(píng)價(jià)肝功能、腎小球?yàn)V過功能的重要指標(biāo),后者常用于急性腎損傷綜合征診斷.Cd組中上述指標(biāo)均極顯著高于對(duì)照組,這與先前研究結(jié)果一致[14-15],表明Cd暴露導(dǎo)致肝、腎功能障礙.研究結(jié)果表明,經(jīng)Se、Ca單獨(dú)及聯(lián)合膳食干預(yù),Cd暴露所致小鼠肝腎功能障礙得到有效緩解,并發(fā)現(xiàn)在高Se干預(yù)基礎(chǔ)上,添加適量Ca對(duì)小鼠肝腎功能的保護(hù)作用更強(qiáng).結(jié)合此前研究,Ca和Se對(duì)肝腎功能的保護(hù)作用與它們對(duì)氧化應(yīng)激狀態(tài)的調(diào)節(jié)作用有關(guān)[10,16].Cd在生物體內(nèi)破壞正常氧化還原平衡狀態(tài),增加活性氧(ROS),消耗細(xì)胞內(nèi)GSH含量和抗氧化酶,增強(qiáng)脂質(zhì)過氧化,致使脂質(zhì)過氧化物MDA含量升高[10,17].本研究佐證上述結(jié)論,發(fā)現(xiàn)Cd組小鼠肝臟和腎臟SOD、GSH-Px和CAT等抗氧化酶活性均顯著降低,GSH含量顯著減少,MDA含量顯著升高,而Se/Ca單獨(dú)和聯(lián)合干預(yù)可使上述指標(biāo)趨近于正常水平.Cd抑制抗氧化酶活性,削弱機(jī)體自由基清除能力,導(dǎo)致肝臟及腎臟氧化應(yīng)激反應(yīng)和脂質(zhì)過氧化,而自由基和過氧化中間產(chǎn)物破壞肝腎細(xì)胞結(jié)構(gòu)完整性和正常功能并進(jìn)一步促使小鼠的肝腎功能受損[18-19].Se可通過激活抗氧化酶、減少脂質(zhì)過氧化和再生谷胱甘肽保護(hù)肝臟和腎臟[17],Ca可通過與Cd競(jìng)爭(zhēng)轉(zhuǎn)運(yùn)蛋白、抑制Cd吸收產(chǎn)生保護(hù)作用[20].本研究發(fā)現(xiàn),相比于Se或Ca單獨(dú)干預(yù),高Se高Ca聯(lián)合干預(yù)對(duì)Cd致肝臟SOD、GSH-Px和GSH與腎臟SOD和MDA變化的拮抗作用最強(qiáng),推測(cè)Se-Ca聯(lián)合干預(yù)緩解Cd致肝腎氧化應(yīng)激反應(yīng)及功能障礙的效果優(yōu)于單一Se或Ca干預(yù).

組織病理學(xué)檢查表明,Cd暴露導(dǎo)致肝腎發(fā)生明顯的病理變化,Se、Ca單獨(dú)及聯(lián)合干預(yù)均可部分緩解Cd致肝臟和腎臟病理損傷,但不能完全消除負(fù)面影響.病理評(píng)估結(jié)果顯示,中Se中Ca、中Se高Ca劑量干預(yù)對(duì)Cd誘導(dǎo)小鼠肝臟和腎臟病理性損傷的緩解作用較單一元素的干預(yù)效果更佳, Se-Ca聯(lián)合干預(yù)僅需較低劑量即可達(dá)到Se或Ca單獨(dú)干預(yù)對(duì)肝腎組織損傷的最佳保護(hù)效果.

4 結(jié)論

4.1 Se、Ca單獨(dú)干預(yù)對(duì)Cd暴露所致肝腎功能障礙、氧化應(yīng)激反應(yīng)和病理損傷的緩解作用呈劑量依賴關(guān)系.

4.2 高Se高Ca聯(lián)合干預(yù)對(duì)Cd暴露所致小鼠肝腎功能障礙和氧化應(yīng)激的緩解效果優(yōu)于單一元素干預(yù).

4.3 較低劑量聯(lián)合膳食干預(yù)即可達(dá)到或超過高水平Se或Ca單獨(dú)干預(yù)對(duì)Cd致肝腎組織病理損傷的最優(yōu)保護(hù)效果.

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Alleviating cadmium toxicity to liver and kidney of mice with dietary supplementation of selenium and calcium in combination.

WU Yang-yang1, PENG Xiang-wen1, SHI Ke-xin1, KUANG Wen-jie1, SUN Hong2, HUANG Lei1*

(1.State Key Laboratory of Pollution Control and Resource Reuse, School of Environment, Nanjing University, Nanjing 210023, China；2.Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210023, China)., 2022,42(3)：1379～1384

To explore the mitigation role of dietary selenium (Se) and calcium (Ca) supplementation in combination in alleviating the biological toxicity of Cd, an in vivo mouse bioassay was performed. Mice (BALB/c,= 88) that were exposed to Cd via diets at the same concentration of 2mg/kg were randomly divided to 19groups of dietary supplementation of low, medium, and high concentrations of Se and Ca in diets alone or in combination. The growth and development of mice, liver and kidney function, oxidative stress state and histopathological changes of the mice were measured after 30days of intervention. Results showed that the combined intervention of Se-Ca could effectively alleviate the growth retardation of mice caused by Cd exposure. In terms of liver and kidney function and oxidative stress, the combined intervention had a stronger protective effect on AST, GSH, SOD, GSH-Px in the liver and BUN, MDA and SOD in the kidney of mice than single Se or Ca intervention. Additionally, a lower dietary concentration of Se and Ca in combination alleviated pathological damage at a similar extent to that of a high concentration of Se or Ca alone. In general, Se-Ca dietary intervention in combination effectively alleviated the growth retardation and liver and kidney toxicity of mice caused by Cd exposure, and the effect was stronger than that of single element intervention.

cadmium；dietary selenium and calcium supplement；dietary intervention；liver and kidney damage

X174

A

1000-6923(2022)03-1379-06

吳楊洋(1998-),男,江蘇鹽城人,南京大學(xué)環(huán)境學(xué)院博士研究生,主要從事環(huán)境健康風(fēng)險(xiǎn)評(píng)估研究.發(fā)表論文4篇.

2021-08-06

國(guó)家重點(diǎn)研發(fā)計(jì)劃項(xiàng)目(2019YFC1805105);江蘇省自然科學(xué)基金資助項(xiàng)目(BK20201186);國(guó)家自然科學(xué)基金資助項(xiàng)目(41822709, 71921003)

*責(zé)任作者, 教授, huanglei@nju.edu.cn