來子陽，胡獻(xiàn)剛，周啟星

南開大學(xué)環(huán)境科學(xué)與工程學(xué)院環(huán)境污染過程與基準(zhǔn)教育部重點實驗室，天津300071

納米材料對鼠科動物的生殖毒性及致毒機(jī)理

來子陽，胡獻(xiàn)剛*，周啟星

南開大學(xué)環(huán)境科學(xué)與工程學(xué)院環(huán)境污染過程與基準(zhǔn)教育部重點實驗室，天津300071

納米材料是近幾年應(yīng)用越來越多的一種新型材料,因此國內(nèi)外科研單位對其毒性的研究也逐年增加。但是目前對鼠科動物生殖毒性及其機(jī)理的了解還相對較少,亟需大量研究填補(bǔ)此領(lǐng)域的空白。本文主要從親代和子代2個方面闡述了納米材料對鼠科動物的生殖毒性,從不同生物水平等方面概述了納米材料對親子兩代鼠科動物的損傷效應(yīng)及可能的機(jī)制。最后,試探性地提出了今后在納米材料領(lǐng)域?qū)κ罂苿游锷扯拘缘难芯恐攸c。

納米材料；鼠科動物；親代；子代；生殖毒性；致毒機(jī)理

隨著納米科學(xué)技術(shù)的飛速發(fā)展,納米材料因其獨特的異于塊體材料的光、電、磁、熱等理化性質(zhì),逐漸滲透到各個產(chǎn)業(yè)領(lǐng)域。納米技術(shù)主要應(yīng)用于軍事[1-2],醫(yī)療[3-6],環(huán)境[7-8]等領(lǐng)域,根據(jù) Woodrow Wilson國際學(xué)者中心對全世界納米技術(shù)項目的統(tǒng)計,納米技術(shù)商品的數(shù)量逐年穩(wěn)定上升。納米材料的出現(xiàn)推進(jìn)了人類科技發(fā)展的進(jìn)程,但是尺寸極小的納米顆粒極大的增加了人類攝入的幾率,不僅職業(yè)人群暴露而且非職業(yè)人群也存在暴露,因此它的負(fù)面作用也愈來愈受到人們的關(guān)注。許多環(huán)境學(xué)家開展了納米材料的毒性研究,并且發(fā)現(xiàn)這種材料可以引起動物機(jī)體的氧化損傷,炎癥效應(yīng)等[9]。此外,還有研究表明納米顆?？梢苑e累于動植物體內(nèi)[10-11],進(jìn)入食物鏈或增加暴露量對人類或生態(tài)平衡產(chǎn)生不良影響。

鼠科動物作為性價比最高且與人類很接近的模式生物,為人類了解各種各樣納米材料的毒性提供了良好的條件,大部分納米材料的生物效應(yīng)通過鼠科動物實驗逐漸被人們所了解,例如口入銀納米顆?？梢砸鹦∈蟛糠纸M織基因組不穩(wěn)定性及DNA損傷[12],氧化石墨烯可以阻礙哺乳期幼鼠的生長發(fā)育[13]等等。納米材料被人類吸收后可能對本身有一定的不良作用,但是對我們的子孫后代是否會有惡性效應(yīng),對后代的生長發(fā)育有無阻礙作用,甚至改變?nèi)祟惖幕蚪M,這些都是不可忽視的問題。對鼠科動物的一般毒性研究較為廣泛,然而對生殖毒性的了解相對甚少。基于此,本文綜述了近年來關(guān)于納米材料對鼠科動物生殖毒性的研究工作,包括對親代生殖系統(tǒng)的效應(yīng),對子代生長發(fā)育的不良影響,并對未來的研究重點進(jìn)行嘗試性展望,以期能夠為納米材料的生殖毒性研究提供一定的參考價值。

1 納米材料對親代鼠科動物的生殖毒性(Reproductive effects of nanomaterials on parental murine)

納米材料一般先分布于鼠科動物的各個器官,而后通過細(xì)胞運(yùn)輸或破壞細(xì)胞膜結(jié)構(gòu)進(jìn)入細(xì)胞內(nèi),進(jìn)而對胞內(nèi)基因、蛋白造成損傷,使得基因表達(dá)及激素、酶類分泌水平的改變反過來導(dǎo)致細(xì)胞水平(精子、卵細(xì)胞等)及器官水平的損傷(如圖1所示)。

1.1 對親代雄鼠的生殖毒性

對于雄鼠來說,睪丸及附睪是納米顆粒主要作用的生殖部位,且研究表明大部分納米顆粒均可通過不同方式到達(dá)雄鼠的生殖器官或組織,例如睪丸,附睪及生精小管等[14-17]。有些納米顆粒的粒徑可決定該種材料是否可以進(jìn)入生殖器官,Morishita等[18]給小鼠連續(xù)2 d靜脈注射相同劑量(0.8mg·d-1)的70 nm和300 nm SiO2,通過透射電鏡觀察發(fā)現(xiàn)在支持細(xì)胞,精母細(xì)胞及其細(xì)胞核內(nèi)均有70 nm的SiO2,然而在睪丸中卻沒有發(fā)現(xiàn)300 nm的SiO2。小粒徑(≤110 nm左右)的銀納米顆?？梢赃M(jìn)入睪丸,而粒徑較大(≥323 nm)的銀則沒有進(jìn)入[19-20]。不同狀態(tài)的納米材料也有不同的分布情況,Pfurtscheller等[21]給大鼠傷口涂抹含不同狀態(tài)銀(銀納米顆粒和硝酸銀泡沫)藥物,6周后,睪丸中原子態(tài)的銀比離子態(tài)的積累量多。一些納米顆粒在靶部位的積累量也有時間效應(yīng),例如將200～300 g金納米顆粒單次靜脈注射到大鼠體內(nèi),觀察1 d、1周、1個月、2個月的器官內(nèi)積累量,發(fā)現(xiàn)注射后1個月在睪丸內(nèi)的含量最多[22]。

圖1 納米材料對親代鼠不同生物水平的生殖毒性Fig.1 Reproductive toxicity of different biotic level of nanomaterials on parental murine

納米顆粒進(jìn)入雄鼠體內(nèi)后,部分會通過機(jī)體循環(huán)作用清除出體內(nèi)。雄性大鼠通過呼吸攝入二氧化鈰納米顆粒(11～55mg·m-3),6 h后即可分布于睪丸及附睪,但組織清除速度很慢,暴露后48 h和72 h后的組織內(nèi)清除量很少[23]。van der Zande等[24]使雄性大鼠連續(xù)28 d經(jīng)口攝入銀納米顆粒(90mg·kg-1body weight),染毒后第8周檢測各個器官內(nèi)銀含量,發(fā)現(xiàn)大多數(shù)器官內(nèi)銀都被清除,但是大腦和睪丸卻沒有。Lee等[25]也有同樣的發(fā)現(xiàn),斯普拉格-杜勒大鼠連續(xù)28 d經(jīng)口攝入不同劑量(100mg·kg-1body weight和500mg·kg-1body weight)10 nm和25 nm的銀納米顆粒,之后停止染毒并令大鼠自行恢復(fù)4個月,發(fā)現(xiàn)大多數(shù)組織內(nèi)銀納米顆粒均被清除,但是大腦和睪丸內(nèi)的銀卻沒有被很好的清除。此外有研究表明納米銀可以在小鼠體內(nèi)保留時間超過4個月,而且它的排出具有時間效應(yīng)[26]。Zhang等[27]研究發(fā)現(xiàn)金納米顆粒(5.9mg·kg-1)經(jīng)注射進(jìn)入小鼠后可分布于睪丸等組織,30 d后大部分金被清除,但在染毒后第60天和第90天時發(fā)現(xiàn)睪丸中金含量比30 d時高,后續(xù)研究表明金在前30天中可以穩(wěn)定地積累于肌肉組織中,但在30～90 d中逐漸釋放到血液中,從而可再次到達(dá)睪丸并積累,小鼠攝入納米材料后可能很久才會出現(xiàn)毒性效應(yīng)。

進(jìn)入雄鼠體內(nèi)的納米材料對睪丸,附睪等組織會產(chǎn)生不同程度的影響。例如水溶性的碳納米管可以引起雄性小鼠睪丸內(nèi)氧化應(yīng)激從而降低生精上皮的厚度,但隨時間流逝損傷會自行愈合[28]。給雄性大鼠單次注射200 nm的銀納米顆粒(5mg·kg-1body weight),染毒后的24 h,7 d和28 d均發(fā)現(xiàn)生精小管發(fā)生形態(tài)學(xué)改變,但不會影響睪丸及附睪的重量[29]。Hassankhani等[30]證明10～15 nm的二氧化硅(333.33mg·kg-1body weight)連續(xù)經(jīng)口攝入5 d后可以引起成年雄性小鼠的睪丸損傷。Orazizadeh[31]發(fā)現(xiàn)連續(xù)35 d經(jīng)口攝入300mg·kg-1body weight二氧化鈦納米材料可以促使小鼠的附睪液泡化,生殖細(xì)胞脫皮及分離明顯上升。另外,連續(xù)35 d攝入高劑量(300mg·kg-1body weight)的氧化鋅納米顆?？梢砸餘MRI雄性小鼠附睪液泡化,輸精管直徑核生精上皮高度的下降,從而導(dǎo)致睪丸損傷[32]。Kong等[33]用填胃法使成年雄性大鼠連續(xù)10周經(jīng)口攝入45mg·kg-1body weight鎳納米顆粒(90 nm),導(dǎo)致生精小管的上皮細(xì)胞脫落,管內(nèi)細(xì)胞的混亂排列,以及細(xì)胞凋亡和死亡。

精子是生物傳宗接代的核心細(xì)胞,納米材料到達(dá)睪丸后會影響精子的數(shù)量、質(zhì)量等。Zakhidov等[34]研究發(fā)現(xiàn)金納米顆粒在體內(nèi)長期(56 d)駐留可以影響小鼠初級精母細(xì)胞的染色體但不會引起精原干細(xì)胞的染色體異常。Garcia等[35]給CD1雄性小鼠注射低劑量(1mg·kg-1·dos-1)銀納米顆粒,每隔3天注射1次,共5次,發(fā)現(xiàn)生殖細(xì)胞凋亡現(xiàn)象及間質(zhì)細(xì)胞大小均有明顯變化,沒有損害精原干細(xì)胞,然而可能會影響間質(zhì)細(xì)胞的功能。另外,連續(xù)25 d攝入高劑量的銀(15或30mg·kg-1·d-1)可以降低維斯塔雄性幼鼠頂體精子和質(zhì)膜的完整性及線粒體的活性,提高精子畸形率[36]。Asare等[37]測試了小鼠睪丸細(xì)胞暴露于20 nm和200 nm銀及21 nm二氧化鈦(100μg·mL-1或10μg·mL-1)24 h和48 h后對的生殖細(xì)胞毒性,結(jié)果顯示銀納米顆粒相對于二氧化鈦有更大的細(xì)胞毒性和細(xì)胞抑制性,可以引起細(xì)胞凋亡,壞死。Xu等[38]發(fā)現(xiàn)二氧化硅納米顆粒的長期暴露(20mg·kg-1,每3天注射1次,共注射5次)可以影響雄性小鼠附睪精子中頂體的完整性和生育能力,以及睪丸內(nèi)精原細(xì)胞和精子的正常生理活動,但隨時間可逐漸恢復(fù)正常水平。較高劑量(25或50mg·kg-1)的二氧化鈦納米顆粒(21 nm)可以引起維斯塔大鼠的氧化壓力,從而產(chǎn)生細(xì)胞和基因毒性來影響精子,最終影響精子的受精能力[39],這種納米材料同樣可以導(dǎo)致小鼠附睪精子參數(shù)包括精子數(shù)量,能動性,畸形率明顯改變[31]。銳鈦礦二氧化鈦納米顆粒的短期暴露可引起雄性小鼠精子結(jié)構(gòu)及功能缺陷[40]。Talebi等[32]研究發(fā)現(xiàn)50、300mg·kg-1的氧化鋅納米顆粒可以引起小鼠附睪內(nèi)精子數(shù)量和畸形率的改變,導(dǎo)致精子脫皮及分離現(xiàn)象增多,300mg·kg-1還引起了生殖上皮中多核巨細(xì)胞的形成。Wang等[41]研究發(fā)現(xiàn)每周1次連續(xù)10周注射高劑量(500μg·kg-1)的鈷-鉻納米顆?？梢悦黠@降低成年雄性大鼠附睪精子能動性,發(fā)育能力及濃度水平,增加異常精子的比例。

較小粒徑的納米材料可以造成較大的生殖細(xì)胞毒性。Valipoor等[42]將不同劑量(10,20,40mg·kg-1)的硒化鎘量子點注射到1個月大的雄性小鼠體內(nèi),發(fā)現(xiàn)40mg·kg-1的納米材料導(dǎo)致了精原細(xì)胞,精母細(xì)胞,精子細(xì)胞,成熟精子數(shù)量減少。相同劑量(100mg·kg-1·d-1或者200mg·kg-1·d-1)及暴露時間(18或35 d)條件下,納米點(粒徑3～5 nm)硫化鎘對小鼠的精子損傷要比納米棒(直徑30～50 nm,長度500～1 100 nm)硫化鎘大[43]。金屬類納米材料一般都會對生殖細(xì)胞造成不良影響,但是碳類納米材料中的碳納米管對小鼠精子的數(shù)量及質(zhì)量無明顯影響[28,44]。

納米材料對雄鼠生殖毒性的源頭在于對基因,蛋白的損傷,從而對精子質(zhì)量、數(shù)量、產(chǎn)量或其他生殖相關(guān)細(xì)胞和組織產(chǎn)生不良效應(yīng)。Jia等[45]使產(chǎn)后28天的昆明雄性小鼠連續(xù)42 d口入納米級二氧化鈦(10、50、250mg·kg-1)導(dǎo)致血清睪丸素水平下降,明顯減少了17β-羥化類固醇脫氫酶和細(xì)胞色素P450 17α-羥化類固醇脫氫酶在睪丸中的表達(dá),然而P450-19(一種睪丸素向雌二醇轉(zhuǎn)化的關(guān)鍵酶類)上升,這些結(jié)果表明納米級二氧化鈦可以通過改變睪丸素的合成和轉(zhuǎn)化來影響血清中睪丸素的水平,而且降低的血清睪丸素可能會減少精子形成。Zhao等[46]給小鼠連續(xù)90 d灌胃給藥(2.5、5、10mg·kg-1body weight),發(fā)現(xiàn)二氧化鈦進(jìn)入雄性小鼠睪丸支持細(xì)胞后產(chǎn)生過量活性氧,并發(fā)生脂質(zhì)過氧化反應(yīng),且蛋白和DNA的抗氧化能力也有所下降,相關(guān)損失的酶類都有所改變,也可導(dǎo)致小鼠睪丸內(nèi)與精子形成相關(guān)的基因表達(dá)水平改變,抑制精子形成[47]。此外,這種納米材料還會導(dǎo)致維斯塔大鼠半胱天冬酶-3(一種細(xì)胞凋亡的生物標(biāo)記物)表達(dá)增多,肌酸激酶活性改變和DNA的損傷[39]。Braydich-Stolle等[29,48]發(fā)現(xiàn)銀納米顆粒(1 000～10 000 nanoparticles·mL-1)短時間暴露(24 h)可擾亂精原干細(xì)胞神經(jīng)營養(yǎng)因子基因激酶信號,導(dǎo)致精原干細(xì)胞增殖減少,同時還可以提高大鼠生殖細(xì)胞的DNA損傷水平。金納米顆?？蓴_亂小鼠精子核染色質(zhì)的解凝,對精子質(zhì)量產(chǎn)生不良影響[49],PEG修飾的這種納米材料(45 225mg·kg-1,暴露時間分別為7、14、21、30 d)還可以提升血漿睪丸素水平但無生育影響[50]。

碳類納米材料對雄性小鼠生殖的基因毒性研究相對較少,但目前研究表明大部分毒性都很低。Yoshida等[51]用3種粒徑(14,56,95 nm)的炭黑給小鼠進(jìn)行氣管暴露(0.1mg·mouse-1,每周10次),結(jié)果發(fā)現(xiàn)14、56 nm的顆粒使得血清睪丸素明顯上升,且14 nm的毒性比56 nm的小,與二氧化鈦可減少Sprague-Dawley大鼠的睪丸素的現(xiàn)象相反[52]。高劑量(300mg·kg-1male mouse)長期暴露(30和60 d)納米級氧化石墨烯對一些雄性小鼠重要的附睪酶類包括α-葡糖苷酶,乳酸脫氫酶,谷胱甘肽過氧化物酶以及酸性磷酸酶都無明顯不良作用[53],碳納米管對雄性小鼠主要的性激素水平也無顯著影響[28]。

1.2 對親代雌鼠的生殖毒性

同樣,納米材料對雌鼠的生殖系統(tǒng)或多或少也有毒性效應(yīng),納米顆?？梢源┩复菩源笫笱?胎盤屏障[54],分布于子宮或胎盤等器官并造成損傷效應(yīng)。Semmler-Behnke等[55]給懷孕大鼠靜脈注射不同粒徑(1.4、18、80 nm)和劑量(3、5、27μg·rat-1)的金納米顆粒,24 h后發(fā)現(xiàn)粒徑越大積累量越小,在羊水中1.4 nm的金比其他2種含量多2個數(shù)量級。Melnik等[56]通過灌胃法使孕期或哺乳期的大鼠攝入35 nm左右1.69～2.21mg·kg-1銀納米顆粒2周后,通過同位素示蹤法發(fā)現(xiàn)銀可以通過胎盤遷移至母乳中；在哺乳期雌鼠體內(nèi),給藥后48 h母乳中總累積量超過(1.94±0.29)%。還有研究表明納米顆粒很容易穿過陰道壁到達(dá)雌性小鼠的生殖系統(tǒng)[57],小粒徑(≤ 40 nm)的磁性氧化鐵納米顆粒很容易進(jìn)入小鼠子宮[58]。高劑量(20mg·kg-1body weight)短期(24 h內(nèi))暴露氧化多壁碳納米管可降低母鼠血清孕酮的水平,提高血清雌二醇的水平；同時,這種納米材料還會積累于體內(nèi),導(dǎo)致較高的流產(chǎn)率,且隨時間毒性效應(yīng)逐漸降低[59]。

小粒徑的二氧化硅納米顆粒和二氧化鈦可以引起雌性小鼠妊娠并發(fā)癥,然而較大粒徑的二氧化硅(300、1000 nm)卻沒有此效應(yīng)[60]。同時,納米級的二氧化鈦還可以引起雌性小鼠生殖功能的紊亂,Zhao等[61]給雌性小鼠連續(xù)90 d灌胃給藥(2.5、5及10mg·kg-1),發(fā)現(xiàn)二氧化鈦可存儲于子房內(nèi),導(dǎo)致胰島素生長因子2,表皮生長因子,腫瘤壞死因子α,組織纖溶酶原激活物,白介素-1β,白介素-6,脂肪酸合成酶及乙型跨膜糖蛋白的表達(dá)的明顯增加；降低了胰島素生長因子-1,黃體化激素,抑制素α,分化因子9在小鼠子房中的表達(dá)水平,從而導(dǎo)致了子房相對重量及生育能力下降,血清參數(shù)和荷爾蒙水平的改變,閉鎖卵泡改變增加,還有炎癥和細(xì)胞壞死的現(xiàn)象。此外,交配后的雌性小鼠連續(xù)2周吸入較高劑量(230mg CdO·m-3)的鎘聯(lián)合氧化鎘納米顆粒會導(dǎo)致懷孕率下降,延遲體重的增加,改變胎盤的重量[62]。成年雌性大鼠長期(90 d)暴露于鎳納米顆粒(45mg·kg-1body weight)可以提高促卵泡激素和促黃體激素的水平,降低雌二醇的水平。在子房內(nèi)發(fā)現(xiàn)淋巴球增多,血管擴(kuò)張及充血,炎性細(xì)胞浸潤,以及凋亡細(xì)胞增加等現(xiàn)象[33]。

金屬類的納米材料對雌性小鼠生殖毒性較高,而碳類納米材料對鼠科動物的生殖毒性較低。雌性小鼠懷孕后第8～18天暴露于炭黑納米顆粒(42mg·m-3)可以導(dǎo)致肺部出現(xiàn)永久性炎癥,但對妊娠期和哺乳期的母鼠無不良影響[63]。暴露于碳納米管(總劑量268μg)的妊娠期(暴露時間:第8、11、15、18天)雌性小鼠生育第1胎有較短的延遲現(xiàn)象[64],另外有研究表明巨噬細(xì)胞受體可以提高中國倉鼠卵巢細(xì)胞對碳納米管的吸收[65]。

2 對子代鼠科動物的生殖毒性 (Reproductive effects of nanomaterials on offspring murine)

外源化合物進(jìn)入到人體體內(nèi)可能會有一定的損害效應(yīng),但更引人關(guān)注的則是這些物質(zhì)是否會對人類的后代造成不良影響。因此絕大多數(shù)鼠類生殖毒性的研究重點放在了對子代的效應(yīng)上。

對于懷孕的雌鼠,大部分納米顆?？梢源┩柑ケP-血液屏障從而到達(dá)胎兒體內(nèi)并積累于此,對子代胚胎期、產(chǎn)后的生長發(fā)育產(chǎn)生不良影響。例如雌性小鼠交配后第4.5天到第16.5天空氣暴露鎘聯(lián)合氧化鎘納米顆粒在此期間胎兒體內(nèi)可以檢測到鎘,雖然在交配后17.5 d胎兒體內(nèi)沒有檢測到納米顆粒,但對子代小鼠后期的發(fā)育還是造成了延緩效應(yīng)[62]。雌性大鼠經(jīng)灌胃攝入35 nm左右1.69～2.21mg·kg-1銀納米顆粒后,在胎兒體內(nèi)的積累量占總攝入劑量的0.085%～0.147%[56]。金納米顆粒(0.9～7.2mg Au·g-1body weight)被懷孕小鼠攝入(懷孕后第5.5～15.5天)后,胎兒體內(nèi)的金含量隨時間逐漸減少,而在胚胎外組織則翻倍增長[66]。妊娠期第9天的母鼠經(jīng)口攝入二氧化鈦或者銀納米顆粒(100或1 000mg·kg-1)都可以顯著增加子代小鼠的畸形率和死亡率,且二氧化鈦還可以降低子代小鼠的發(fā)育成功率[67]。暴露于氧化鋅納米顆粒的雄性(500mg·kg-1·d-1,交配前連續(xù)染毒6周)及雌性大鼠(500mg·kg-1·d-1,交配前2周到孕期第4天)會對子代造成一系列不同影響,產(chǎn)子數(shù)量及子代體重減少,且主要分布于子代鼠的肝臟和腎臟[68]。Hong等[69-70]研究發(fā)現(xiàn)在孕期第5～19天給斯普拉格-道利雌性大鼠填胃給藥(400mg·kg-1·d-1)可導(dǎo)致胎兒畸形率顯著上升。Di Bona等[71]發(fā)現(xiàn)帶不同電荷的氧化鐵納米顆粒(2.5mg Fe·kg-1body mass,孕期第9～16天每天注射1次)都可以穿過胎盤進(jìn)入胎兒體內(nèi),帶正電荷的納米顆粒有更多的分布及毒性效應(yīng)。Philbrook等[72]研究了功能化碳納米管對胚胎期子代小鼠的影響,發(fā)現(xiàn)母鼠在孕期第9天單次攝入10mg·kg-1碳納米管在子鼠器官發(fā)生期顯著增加了再吸收的數(shù)量,并且導(dǎo)致了胎兒形態(tài)學(xué)及骨骼的畸形。Fujitani等[73]也證明多壁碳納米管對胎兒具有致畸性,且另有研究發(fā)現(xiàn)單壁碳納米管對子代小鼠的致畸性比原始碳納米管要高[74]。

大腦是動物的核心器官,因此絕大多數(shù)對子代影響的研究集中于神經(jīng)系統(tǒng)。給孕期小鼠(總劑量0.4mg)皮下注射二氧化鈦納米顆粒會導(dǎo)致子代小鼠大腦皮層,嗅球以及一些與多巴胺聯(lián)系緊密區(qū)域發(fā)生改變,與紋狀體相關(guān)的基因有差異性表達(dá),而且與多巴胺神經(jīng)系統(tǒng)有關(guān)的區(qū)域及前額區(qū)域在嬰兒期調(diào)節(jié)異常,而且還會使大腦嗅覺區(qū)出現(xiàn)大量半胱天冬酶-3陽性細(xì)胞[75-76]。給孕期第2～21天的雌性大鼠灌胃給藥二氧化鈦(每日給藥100mg·kg-1body weight)可以通過降低子代海馬細(xì)胞的增值,顯著損傷學(xué)習(xí)和記憶能力[77]。Fatemi等[78]通過給雌性大鼠口入銀納米顆粒(25mg·kg-1body weight)也可以引起子代腦部細(xì)胞的氧化壓力和凋亡。Okada等[79]研究發(fā)現(xiàn)給孕期小鼠皮下注射氧化鋅納米顆粒(第5、8、11、14、17天,每天100μg·mouse-1)可以改變子代小鼠大腦中單胺能神經(jīng)遞質(zhì)的水平,因此氧化鋅可能會通過母體到達(dá)子代體內(nèi)影響其神經(jīng)系統(tǒng)。2014年,Onoda等[80]通過鼻內(nèi)滴注的方法使孕期母鼠攝入超細(xì)的炭黑納米顆粒(孕期第5～9天,總劑量190mg·kg-1body weight),發(fā)現(xiàn)子代小鼠大腦血管周邊巨噬細(xì)胞粒斑變大,星形膠質(zhì)細(xì)胞膠質(zhì)纖維酸性蛋白表達(dá)水平上升,通過電鏡觀察發(fā)現(xiàn)一些巨噬細(xì)胞粒斑的蜂窩結(jié)構(gòu)和星形細(xì)胞有腫脹現(xiàn)象。較大粒徑的碳納米管可穿過小鼠的血液-胎盤屏障,限制胎兒的發(fā)育,引起大腦畸形,然而單壁碳納米管和較小粒徑的納米顆粒的胎兒毒性很小[81]。

另外,對子代鼠其他一些重要部位,包括肝臟、肺臟、腎臟也有所研究。2012年,Jackson等[82]通過肺部暴露使孕期小鼠(妊娠期第8～18天)攝入炭黑納米顆粒(總劑量分別為11,54,268μg·animal-1),發(fā)現(xiàn)子代小鼠中雌性的敏感性高于雄性,雌性子代小鼠的細(xì)胞信號,炎癥,細(xì)胞周期和脂類代謝均受到影響,此外,與代謝相關(guān)的基因也有微妙的變化。2013年,他們繼續(xù)研究了二氧化鈦呼吸暴露(妊娠期第8～18天,1 h·d-1,42mg UV-Titan·m-3氣溶膠粉末)于母鼠對子代肝臟的影響,發(fā)現(xiàn)納米顆粒并沒有引起子代小鼠肝臟DNA的斷裂,且蛋白表達(dá)不受影響[83]。Umezawa等[84]將懷孕小鼠(孕期第5～9天)暴露于總劑量100μg的炭黑納米顆粒。收集3周和12周齡的雄性子代小鼠的血液及腎臟組織,檢測了血清中肌酸酐和血尿素氮,結(jié)果表明納米顆粒導(dǎo)致了12周齡子鼠腎臟腎小管細(xì)胞8型膠原蛋白的表達(dá)增加,但3周齡的小鼠并無此現(xiàn)象。孕期母鼠第8～18天暴露于炭黑納米顆粒(42mg·m-3)也會引起子代小鼠的肝臟DNA損傷[63]。

對免疫系統(tǒng)的研究主要針對子代鼠的脾臟。孕期小鼠通過鼻內(nèi)滴注(懷孕后第5～9天,總劑量為190μg·kg-1body weight)接觸炭黑會導(dǎo)致子代小鼠體內(nèi)CD3+(T),CD4+和CD8+細(xì)胞的減少。Il15的表達(dá)水平在雄性子代小鼠脾臟內(nèi)顯著上升,Ccr7和Ccl19在雌雄子鼠體內(nèi)升高,說明母鼠暴露于炭黑后會部分抑制子代小鼠免疫系統(tǒng)的發(fā)育[85]。孕期第9～15天母鼠經(jīng)鼻內(nèi)滴注攝入總劑量為95mg·kg-1body weight炭黑納米顆粒后,引起子代小鼠胸腺細(xì)胞和它們的免疫表型CD4-CD8-和CD4+CD8+細(xì)胞數(shù)量的增加,同時引起總淋巴球的增加,說明母鼠經(jīng)呼吸道攝入納米顆?？赡軐ψ哟坌孕∈笥羞^敏或炎性效應(yīng)[86]。

納米顆粒同樣也可以穿透胎盤進(jìn)入胚胎體內(nèi),積累于子代小鼠的生殖系統(tǒng),并呈現(xiàn)劑量依賴性分布[87],對精子數(shù)量、質(zhì)量等造成影響。交配后第3、7、10、14天的母鼠每天皮下注射0.1mg二氧化鈦納米顆粒同樣也可以影響子代雄性小鼠的生殖參數(shù),導(dǎo)致日精子產(chǎn)量減少[75]。Yoshida等[88]研究發(fā)現(xiàn)母鼠在孕期第7～14天暴露于14 nm的碳納米顆粒(200μg)會導(dǎo)致子代雄性小鼠部分生精小管空泡形成,生精上皮細(xì)胞的細(xì)胞粘附性降低,日精子產(chǎn)量明顯下降并呈現(xiàn)時間效應(yīng)(產(chǎn)后5周下降47%,10周34%,15周32%),且對睪丸、附睪重量,血清睪丸素濃度無明顯影響。產(chǎn)后第5～7天暴露于高劑量(100、200、300mg·kg-1)的磁性氧化鐵納米顆?？蓪?dǎo)致的胎兒生長發(fā)育明顯受阻,且新生胎兒的精原細(xì)胞、精母細(xì)胞、精子細(xì)胞、成熟精子數(shù)量明顯下降[89]。

3 總結(jié)與展望(Summary and prospect)

綜上所述,納米材料可以進(jìn)入鼠科動物體內(nèi),分布于各個器官組織,產(chǎn)生一定的激素或酶類影響生殖系統(tǒng)的正常生理狀況,從而導(dǎo)致生殖器官(睪丸、子宮等),生殖細(xì)胞(精子,卵細(xì)胞)及DNA的損傷并且最終到達(dá)胎兒體內(nèi);另一方面,納米材料可以進(jìn)入懷孕母鼠體內(nèi),并穿過胎盤—血液屏障直接到達(dá)胎兒體內(nèi),影響胎兒在母鼠體內(nèi)的正常生長發(fā)育。同時,胎兒也會反作用于胎盤進(jìn)而對母鼠造成一定影響。納米材料對出生后的幼鼠與母鼠之間也可能存在一定的互相作用(如圖2所示)。

圖2 納米材料對子代鼠可能的擴(kuò)散及毒性機(jī)理Fig.2 Potential transports and toxic mechanism of nanomaterials on offspring murine

對于普通人群來說,接觸納米材料有以下幾種方式:呼吸,飲食,皮膚滲透,藥物注射[90-93]。一般為了達(dá)到治療效果,給人體注射的納米顆粒劑量會稍高一些(約100～200μg·mL-1)[90,94],而其它3種方式暴露的劑量水平都很低(約 10 ng·kg-1body weight·d-1)[93]。有研究表明(100μg·mL-1)銀納米材料可以對人類睪丸細(xì)胞造成一定損傷[37],雖然目前已有大量的哺乳動物毒性實驗來推斷納米材料對人體的可能毒性作用,但是由哺乳動物如何合理科學(xué)外推到人類的健康風(fēng)險的有待于進(jìn)一步研究[95]。隨著納米毒理學(xué)的迅速發(fā)展,人群可能暴露納米顆粒的途徑及其劑量相關(guān)研究的開展,結(jié)合可能的臨床觀察等手段,將填補(bǔ)納米材料誘發(fā)人類生殖毒性效應(yīng)認(rèn)知的空白。

隨著納米材料越來越多地應(yīng)用于我們的日常生產(chǎn)生活當(dāng)中,會有各種各樣的納米顆粒進(jìn)入生態(tài)環(huán)境,被自然界的動植物及微生物所吸收,對自身及后代造成一定影響,進(jìn)而產(chǎn)生不同程度的生態(tài)風(fēng)險。作為促進(jìn)科技迅猛發(fā)展的納米材料,今后需對以下幾個生殖毒性方面進(jìn)行重點探索:

(1)把握好實驗研究中染毒時間及樣品收集時間,納米材料在小鼠體內(nèi)的分布不是固定的,存在機(jī)體自身清除的機(jī)制及納米材料自行遷移的行為,因此需要把握好測試時間,保證盡可能說明納米顆粒的生殖毒性效應(yīng)。

(2)加大鼠科動物生殖毒性研究的廣度、深度。一方面開展新型的納米材料生殖毒性研究,例如石墨烯和氧化石墨烯等,以及同種納米材料不同形貌、粒徑、修飾的生殖毒性效應(yīng)研究；另一方面深入研究不同納米材料對不同生物水平的損傷機(jī)理,包括整體水平,器官水平,細(xì)胞水平及分子水平。一般納米顆粒首先損傷微觀水平,例如細(xì)胞,基因及蛋白,而后才會有其他水平的毒性效應(yīng)。因此應(yīng)該以分子和細(xì)胞水平的損傷機(jī)制研究為主,例如特定蛋白表達(dá)[96],激素分泌等[97],再輔以器官及整體水平的研究。

(3)研究鼠科動物對納米材料的防御機(jī)制及防御極限。探索可接受的無效應(yīng)最高濃度及可能會產(chǎn)生不良效應(yīng)的最小濃度,尋找調(diào)控防御的基因及蛋白,探尋納米材料破壞鼠類防御體系的機(jī)制。

(4)除了研究納米材料對鼠科動物的直接生殖毒性外,還要加強(qiáng)間接毒性的研究,例如納米材料作用于別的器官或組織,產(chǎn)生異常水平的生殖相關(guān)激素從而影響親代鼠的生育能力；再如納米顆粒作用于其他細(xì)胞產(chǎn)生細(xì)胞毒素,經(jīng)遷移到達(dá)生殖系統(tǒng)造成不良效應(yīng)。另外也要加強(qiáng)納米材料對產(chǎn)后母鼠與子代鼠相互作用的影響,例如對母鼠看護(hù),哺乳的影響及子代鼠給母鼠的反饋影響[98]。

(5)研究何種藥物可以緩解或者治愈納米材料引起的小鼠生殖系統(tǒng)損傷,例如β-胡蘿卜素可以降低由二氧化鈦引起的生殖系統(tǒng)的損傷,改善精子數(shù)量及質(zhì)量[31]。

(6)不僅要關(guān)注納米材料對鼠科動物子代的影響,還應(yīng)該著眼于對后代鼠的影響[99-100],將親代鼠與后續(xù)幾代的生命參數(shù)作對比,了解納米材料對物種的長期影響。

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Reproductive Effects and Their Mechanisms of Nanomaterials on Murine

Lai Ziyang,Hu Xiangang*,Zhou Qixing
Key Laboratory of Pollution Processes and Environmental Criteria(Ministry of Education),College of Environmental Science and Engineering,Nankai University,Tianjin 300071,China

26 May 2015 accepted 27 July 2015

Recently,nanomaterials as emerging materials have been applied in various fields,and their potential toxicity has attracted much attention.However,the reproductive effects and their mechanisms of nanomaterials on murine are unclear.Therefore,it is necessary to perform the relevant work to fill the gaps in knowledge.The present review elucidates the reproductive effects of nanomaterials on murine involving parents and offspring,and summarizes the potential mechanisms of toxic effects at different biotic levels.Finally,the future emphases of researches on the reproductive effects of nanomaterials were proposed.

nanomaterials;murine;parent;offspring;reproductive effects;toxic mechanisms

2015-05-26 錄用日期:2015-07-27

1673-5897(2016)1-014-11

X171.5

A

10.7524/AJE.1673-5897.20150526002

來子陽,胡獻(xiàn)剛,周啟星.納米材料對鼠科動物的生殖毒性及致毒機(jī)理[J].生態(tài)毒理學(xué)報,2016,11(1):14-24

Lai Z Y,Hu X G,Zhou Q X.Reproductive effects and their mechanisms of nanomaterials on murine[J].Asian Journal of Ecotoxicology,2016,11(1):14-24(in Chinese)

國家水專項(2012ZX07501002-001)；教育部長江學(xué)者創(chuàng)新團(tuán)隊(IRT13024)；國家自然科學(xué)基金(21577070；21307061)；中國博士后基金(2014M550138；2015T80215)

來子陽(1992-),男,碩士,研究方向為納米材料的毒理效應(yīng),E-mail:laiziyang@mail.nankai.edu.cn

),E-mail:huxiangang@nankai.edu.cn

簡介:胡獻(xiàn)剛(1983-)，男，博士，副教授，主要從事納米材料的環(huán)境健康效應(yīng)及其控制技術(shù)研究，發(fā)表SCI論文22篇。