手性除草劑異丙甲草胺毒理研究進(jìn)展

張 璇，楊瑞麗，柳春紅，孫遠(yuǎn)明，雷紅濤

(廣東省食品質(zhì)量安全重點(diǎn)實(shí)驗(yàn)室 廣東省食品安全檢測(cè)與風(fēng)險(xiǎn)控制工程技術(shù)研究中心，廣東 廣州 510642)

手性除草劑異丙甲草胺毒理研究進(jìn)展

張 璇，楊瑞麗，柳春紅，孫遠(yuǎn)明，雷紅濤

(廣東省食品質(zhì)量安全重點(diǎn)實(shí)驗(yàn)室 廣東省食品安全檢測(cè)與風(fēng)險(xiǎn)控制工程技術(shù)研究中心，廣東 廣州 510642)

異丙甲草胺是目前廣泛使用的酰胺類芽前闊葉雜草防除劑。文章綜述了異丙甲草胺進(jìn)入環(huán)境后對(duì)非靶標(biāo)生物急性毒性、慢性毒性的對(duì)映體選擇性差異，這種選擇性差異與生物體的吸收及代謝密切相關(guān)。最后對(duì)異丙甲草胺手性毒理的未來(lái)研究進(jìn)行了展望。

異丙甲草胺；對(duì)映體選擇性；毒性

異丙甲草胺[2-乙基-6-甲基-N-(1-甲基-2-甲氧乙基)氯代乙酰替苯胺]，通用名為metolachlor，是一種酰胺類雜草防除劑[1]，因其具有廣譜、高效、選擇性強(qiáng)等特點(diǎn)，可廣泛應(yīng)用于70多種作物田的雜草防除[2]。異丙甲草胺有4種光學(xué)異構(gòu)體，分別為aS,1S-、aR,1S-、aR,1R-和aS,1R-(圖1)。目前市場(chǎng)上常見的異丙甲草胺商品化產(chǎn)品有2種：一種是外消旋異丙甲草胺(Rac-metolachlor)，即4種異構(gòu)體同時(shí)存在，又稱都爾、杜爾、杜耳、稻樂思、屠莠胺、莫多草、甲氧毒草胺；另一種是S-異丙甲草胺(S-metolachlor)，又稱精異丙甲草胺、金都爾，去除了2個(gè)非活性的R-(aR,1R-和aS,1R-)并富集了S-構(gòu)型異構(gòu)體。S-異丙甲草胺的沸點(diǎn)、蒸汽壓、穩(wěn)定性、溶解度、防治雜草種類、吸收與傳導(dǎo)、代謝與降解等特性均與Rac-異丙甲草胺相似[3]。異丙甲草胺95%的除草活性來(lái)自S-異構(gòu)體(aS,1S-和aR,1S-異丙甲草胺)[4]，所以S-異丙甲草胺的有效用量比Rac-異丙甲草胺低35%～38%[5]。但同時(shí)，隨著異丙甲草胺的廣泛應(yīng)用，造成環(huán)境生物與其接觸，由此造成持續(xù)低水平暴露下的非靶標(biāo)毒性，而這些毒性也呈現(xiàn)出不同程度的對(duì)映體差異性[6-7]。

1 異丙甲草胺急性毒性的對(duì)映體選擇性

1.1 異丙甲草胺對(duì)動(dòng)物的對(duì)映體選擇性

異丙甲草胺在使用過程中可能會(huì)對(duì)非靶標(biāo)生物造成影響或危害，如異丙甲草胺泄漏、污染、殘留等情況下，動(dòng)植物及人類可能在短時(shí)間內(nèi)接觸到高濃度的異丙甲草胺，繼而發(fā)生急性中毒[8]。Rac-異丙甲草胺對(duì)雌、雄大鼠急性經(jīng)口毒性的半數(shù)致死量(LD50)分別為2 330 mg/kg和3 160 mg/kg[9]，S-異丙甲草胺原藥對(duì)雄、雌性大鼠亞慢性經(jīng)口染毒劑量分別為158. 0 mg/kg和632. 0 mg/kg 及以上時(shí),對(duì)大鼠有毒性效應(yīng)[10]。S-異丙甲草胺對(duì)水生大型蚤和蚯蚓的LD50分別為51.2 mg/kg[11]和34.63 mg/kg[12](表1)。說(shuō)明水生動(dòng)物對(duì)異丙甲草胺的毒性敏感度較哺乳動(dòng)物大鼠的更高。

注：1.EC50的單位為mg/L；2.LD50的單位為mg/kg。

Note:1.The unit of EC50is mg/L;2.The unit of LD50is mg/kg.

1.2 異丙甲草胺對(duì)水生植物的對(duì)映體選擇性

小球藻和綠藻暴露在Rac-異丙甲草胺環(huán)境下96 h，半數(shù)最大效應(yīng)濃度(EC50)分別達(dá)到18.926 mg/L[13]和5.508 mg/L[14]。羊角月牙藻暴露于Rac-異丙甲草胺條件下72 h，EC50低至0.056 mg/L[15]。S-和Rac-異丙甲草胺對(duì)斜生柵藻、粉核小球藻和水稻的半數(shù)最大效應(yīng)濃度(EC50)存在明顯的差異，對(duì)于柵藻，Rac-異丙甲草胺表現(xiàn)出的毒性效應(yīng)比S-異丙甲草胺更強(qiáng)(表1)。這表明異丙甲草胺對(duì)多種不同非靶標(biāo)生物均表現(xiàn)出比較明顯的急性毒性。

2 異丙甲草胺慢性毒性的對(duì)映體選擇性

對(duì)于異丙甲草胺的慢性毒性，現(xiàn)有研究多以胚胎細(xì)胞、肝癌細(xì)胞、肝微粒體、水生魚類及哺乳動(dòng)物個(gè)體等為生物模型進(jìn)行評(píng)價(jià)，并且在發(fā)育毒性、免疫毒性、肝毒性等方面已有部分研究結(jié)果(表2)。

2.1 發(fā)育毒性

胚胎和幼年時(shí)期是動(dòng)物發(fā)育的一個(gè)重要敏感期，該時(shí)期外源性污染物的吸收和積累可能會(huì)嚴(yán)重影響到胚胎發(fā)育和器官形成，導(dǎo)致身體畸形甚至死亡等不可逆轉(zhuǎn)的傷害。2.88 ng/mL的S-異丙甲草胺即可顯著減少雞胚胎細(xì)胞的數(shù)量[20]。在小鼠胚胎細(xì)胞培養(yǎng)液中加入100 ng/mL Rac-異丙甲草胺，72 h后細(xì)胞凋亡率顯著升高，囊胚發(fā)育受到抑制，胚胎細(xì)胞數(shù)減少[21]。10-3mol/L的Rac-異丙甲草胺對(duì)斑馬魚胚胎即表現(xiàn)出明顯的致死、致畸、抑制發(fā)育等不良影響，并且呈現(xiàn)一定的時(shí)間劑量依賴性[22](表2)。

2.2 免疫毒性

Rac-異丙甲草胺具有免疫毒性，主要表現(xiàn)為對(duì)體液免疫和非特異性免疫功能的抑制作用，影響淋巴細(xì)胞活力和分泌功能及抗體生產(chǎn)量[23]。2.0 μg/mL的Rac-異丙甲草胺即可使小鼠骨髓嗜多染紅細(xì)胞有絲分裂指數(shù)顯著下降，40 μg/mL的Rac-異丙甲草胺則能觀察到該細(xì)胞數(shù)量明顯減少[24]。Rac-異丙甲草胺還能降低小鼠脾臟體比，抑制細(xì)胞活力和降低抗體水平，抑制B淋巴細(xì)胞功能，對(duì)小鼠體液免疫功能表現(xiàn)出抑制作用；另外，小鼠腹腔巨噬細(xì)胞吞噬雞紅細(xì)胞試驗(yàn)也發(fā)現(xiàn)，Rac-異丙甲草胺可使小鼠巨噬細(xì)胞吞噬率明顯降低，且存在劑量-效應(yīng)關(guān)系，對(duì)小鼠非特異性免疫功能也表現(xiàn)出一定毒性[23]。3 ng/mL的 Rac-異丙甲草胺對(duì)人淋巴細(xì)胞數(shù)量無(wú)影響[25]。Mathias等[26]研究發(fā)現(xiàn)，50 mg/kg的S-異丙甲草胺可引起雄性大鼠生殖系統(tǒng)內(nèi)分泌的變化。

2.3 肝毒性

在大鼠體內(nèi)細(xì)胞色素P450酶系作用下，Rac-異丙甲草胺能代謝為具有致癌作用的二烷基醌亞胺[27]。周明等[10]對(duì)S-異丙甲草胺原藥進(jìn)行大鼠亞慢性(90 d)經(jīng)口毒性試驗(yàn)，在整個(gè)染毒期間，高劑量 (632 mg/kg) 組經(jīng)病理組織學(xué)檢查發(fā)現(xiàn)大鼠肝細(xì)胞輕度水腫，而其他各臟器未見病理改變，說(shuō)明受檢樣品高劑量組對(duì)大鼠肝臟有一定影響。從分子水平上研究手性農(nóng)藥的肝毒機(jī)制也已逐漸展開，如以肝癌細(xì)胞Hep G2為體外模型，發(fā)現(xiàn)Rac-異丙甲草胺能對(duì)調(diào)節(jié)細(xì)胞周期蛋白的表達(dá)起到顯著抑制作用，影響細(xì)胞正常增殖，進(jìn)而引起該細(xì)胞凋亡[28]。近年來(lái)，以癌細(xì)胞、原代細(xì)胞等為研究模型的體外監(jiān)測(cè)技術(shù)在毒理學(xué)領(lǐng)域的應(yīng)用日益廣泛，它們不但可以減少實(shí)驗(yàn)動(dòng)物用量，實(shí)現(xiàn)快速、便捷、高通量分析，而且對(duì)于解釋被測(cè)物質(zhì)毒理學(xué)效應(yīng)的分子機(jī)理也有重要意義[29-32]。目前，研究者多是分析Rac-異丙甲草胺的肝毒機(jī)制[33]，對(duì)異丙甲草胺毒性的對(duì)映體選擇差異性研究尚未涉及。

2.4 其他毒性

也有其他研究者以小鼠個(gè)體、水生動(dòng)物及人為生物模型，研究Rac-異丙甲草胺的遺傳毒性、甲狀腺毒性、肺毒性和前列腺毒性作用，發(fā)現(xiàn)Rac-異丙甲草胺對(duì)甲狀腺、肺和前列腺有很弱的毒性作用，無(wú)遺傳毒性[9-10,34-36]。

3 異丙甲草胺吸收及代謝的對(duì)映體選擇性

3.1 生物吸收的對(duì)映選擇性

手性農(nóng)藥對(duì)映體選擇性的跨膜作用和特異性的生物吸收，使得實(shí)際產(chǎn)生毒性作用的單一對(duì)映體的含量與進(jìn)入生物體內(nèi)的初始含量并不一致，其中單一對(duì)映體的累積在生物體內(nèi)被廣泛觀察到[37]。 Rac-和S-異丙甲草胺對(duì)斜生柵藻細(xì)胞膜通透性的影響存在選擇性差異，Rac-異丙甲草胺對(duì)普通核小球藻和斜生柵藻的EC50,96 h時(shí)分別是S-異丙甲草胺的 2.25 和1.81倍[16]。Rac-和S-異丙甲草胺處理玉米和水稻幼苗根系后，玉米和水稻質(zhì)膜通透性均顯著增加，且通透性與2種農(nóng)藥濃度都呈正相關(guān)，但S-對(duì)映體處理后的質(zhì)膜通透性顯著大于Rac-對(duì)映體處理[38]。在透射電子顯微電鏡(Transmission electron microscope，TEM)下觀察經(jīng)Rac-和S-異丙甲草胺處理的蛋白核小球藻，發(fā)現(xiàn)二者均有質(zhì)壁分離現(xiàn)象，并且在葉綠體中聚集了許多淀粉粒，在胞質(zhì)中有一些脂質(zhì)小滴和一些未知的電子不透明沉淀小體，還有大量的處于分裂狀態(tài)或未完全分裂即已死亡的細(xì)胞，這些都是細(xì)胞受損的信號(hào)，S-異丙甲草胺處理組的形態(tài)變化更為嚴(yán)重[19]。這些研究說(shuō)明，Rac-和S-異丙甲草胺均會(huì)破壞受試生物的細(xì)胞結(jié)構(gòu)，抑制細(xì)胞的正常生長(zhǎng)和代謝，且Rac-和 S-異丙甲草胺表現(xiàn)出立體選擇差異性，S-異丙甲草胺對(duì)受試生物的毒性比Rac-異丙甲草胺的毒性更大。

3.2 生物代謝的對(duì)映選擇性

手性農(nóng)藥進(jìn)入環(huán)境后，在生物體的吸收、轉(zhuǎn)運(yùn)、分布及代謝中不僅可生成多種降解產(chǎn)物，而且會(huì)表現(xiàn)出對(duì)映體選擇性差異，其代謝產(chǎn)物可作為母體在環(huán)境中的風(fēng)險(xiǎn)評(píng)估指標(biāo)，研究手性化合物在生物體內(nèi)的轉(zhuǎn)變過程對(duì)解釋選擇性毒性作用機(jī)制非常重要[39]。Rac-及S-異丙甲草胺在玉米根系中的代謝產(chǎn)物是一致的，它們?cè)谟衩赘抵械拇x過程分為3步，依次是氯離子被羥基取代、脫羥基作用和甲氧基被羥基取代(圖2)，可能對(duì)應(yīng)的降解產(chǎn)物分別為羥基化異丙甲草胺(Hydroxymetolachlor)、脫氯異丙甲草胺(Deschlorometolachlor)和丙醇脫氯異丙甲草胺(Deschlorometolachlor propanol)[38]。玉米根系對(duì)低濃度Rac-和S-異丙甲草胺消解(根系吸收和降解)較快，且S-異丙甲草胺的消解速率快于Rac-異丙甲草胺，說(shuō)明2種農(nóng)藥在玉米根系的消解存在立體選擇差異性[38]。但是，母體的降解并不意味著生態(tài)風(fēng)險(xiǎn)的降低或消逝，這些降解產(chǎn)物是新型污染物，其環(huán)境行為和毒理特性仍是未知的[30,40]。Rac-異丙甲草胺在大鼠體內(nèi)代謝則生成具有致瘤作用的二烷基醌亞胺[27,41]，這說(shuō)明手性除草劑異丙甲草胺在不同生物體內(nèi)的代謝產(chǎn)物可能具有對(duì)映體選擇性。

4 展 望

我國(guó)目前使用的手性農(nóng)藥約占農(nóng)藥市場(chǎng)份額的40%[42]。手性除草劑異丙甲草胺作為一種疏水性持久有機(jī)物，其在營(yíng)養(yǎng)級(jí)中有一個(gè)從低級(jí)到高級(jí)的積累過程[43]，且在一條食物鏈的循環(huán)過程中還會(huì)伴隨著異丙甲草胺在生物體內(nèi)的對(duì)映選擇性富集放大[37]。當(dāng)異丙甲草胺對(duì)映體進(jìn)入生態(tài)環(huán)境或生物體后，若依據(jù)非手性分析方法對(duì)其分析，所得信息可能會(huì)與實(shí)際生理效應(yīng)并不相符，因此深入研究對(duì)映體選擇性毒性，將為手性農(nóng)藥的環(huán)境安全和人體健康風(fēng)險(xiǎn)評(píng)價(jià)提供不可或缺的技術(shù)支持和科學(xué)依據(jù)[44]。盡管已有不少國(guó)內(nèi)外科學(xué)家開展了相關(guān)的研究工作，但是要得出普遍的規(guī)律，還需要更多研究結(jié)果的支撐。

由于不同對(duì)映體對(duì)靶標(biāo)生物具有不同的生物作用，在關(guān)注對(duì)靶標(biāo)生物具有活性的對(duì)映異構(gòu)體的同時(shí)，卻忽略了處理其在環(huán)境或是生物體中對(duì)非靶標(biāo)生物具有毒性效應(yīng)的單一對(duì)映異構(gòu)體[45]。實(shí)踐證明，手性農(nóng)藥的不同對(duì)映異構(gòu)體對(duì)于不同生物體的毒性存在顯著差異，這種選擇差異性既取決于手性農(nóng)藥的對(duì)映異構(gòu)體，亦與生物體內(nèi)參加作用的生物大分子相關(guān)[46-47]。而且，目前對(duì)于異丙甲草胺的手性分析主要集中在對(duì)映體分?jǐn)?shù)(EF值)或?qū)τ丑w比(ER值)的測(cè)定上，其對(duì)映體在環(huán)境或生物體內(nèi)代謝機(jī)理及毒理學(xué)機(jī)制等諸多方面亟待加強(qiáng)[48]。今后的研究可以從對(duì)映體水平結(jié)合物種、器官等因素進(jìn)行綜合評(píng)價(jià)：一是可以從對(duì)映體間的毒性差異來(lái)展開研究；二是可針對(duì)不同物種或器官來(lái)評(píng)價(jià)對(duì)映體不同的毒性行為；三是既包括觀察對(duì)映體的選擇性代謝，也包含深入認(rèn)識(shí)不同對(duì)映體對(duì)環(huán)境和生物體的生化影響過程，最終要深入到代謝機(jī)理、蛋白和基因水平上，闡述產(chǎn)生手性對(duì)映體選擇性的根源。只有在對(duì)映體水平上研究異丙甲草胺的生物活性行為，才能更準(zhǔn)確地評(píng)估其生態(tài)風(fēng)險(xiǎn)性以及對(duì)人類健康的影響，對(duì)異丙甲草胺的合理使用也才有較好的指導(dǎo)意義，從而減少其非活性部分對(duì)環(huán)境及生物產(chǎn)生的危害和風(fēng)險(xiǎn)，減少資源浪費(fèi)[49-50]。

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Progress in toxicity of chiral herbicide metolachlor

ZHANG Xuan,YANG Rui-li,LIU Chun-hong,SUN Yuan-ming,LEI Hong-tao

(GuangdongProvincialKeyLaboratoryofFoodQualityandSafety,ResearchCenterofEngineeringandTechniqueforFoodSafetyDetectionandRiskControl,Guangzhou,Guangdong510642,China)

Chiral herbicide metolachlor is widely used for preemergence control of broad-leaved weeds.This review focused on its enantioselective differences of acute and chronic toxicities to non-target organisms after entering the environment.These differences are closely related to biological absorption and metabolism.The developmental trends of future investigations on chiral toxicology were also discussed.

metolachlor;enantioselectivity;toxicity

2013-09-22

廣東省科技計(jì)劃項(xiàng)目(2013B051000072，2012A020100002)；廣東省自然科學(xué)基金項(xiàng)目(S2013030013338)；教育部博士點(diǎn)基金項(xiàng)目(20114404130002)；公益性行業(yè)(農(nóng)業(yè))科研專項(xiàng)(201003008-08)；國(guó)家星火計(jì)劃項(xiàng)目(2011GA780024)

張 璇(1989-)，女，湖北荊州人，碩士，主要從事生物分析化學(xué)研究。E-mail：zhang_xuan_2009@163.com

雷紅濤(1973-)，男，陜西渭南人，教授，博士，主要從事生物分析化學(xué)與分子識(shí)別研究。 E-mail：immunoassay@126.com

時(shí)間:2014-12-12 09:30

10.13207/j.cnki.jnwafu.2015.01.015

S481+.1

A

1671-9387(2015)01-0152-07

網(wǎng)絡(luò)出版地址:http://www.cnki.net/kcms/detail/61.1390.S.20141212.0930.015.html