閆振華，孫紅偉，陸光華

(1.河海大學(xué)淺水湖泊綜合治理與資源開(kāi)發(fā)教育部重點(diǎn)實(shí)驗(yàn)室，江蘇 南京 210098； 2.河海大學(xué)環(huán)境學(xué)院，江蘇 南京 210098)

水體中氟西汀的賦存、累積和生物效應(yīng)研究進(jìn)展

閆振華1,2，孫紅偉1,2，陸光華1,2

(1.河海大學(xué)淺水湖泊綜合治理與資源開(kāi)發(fā)教育部重點(diǎn)實(shí)驗(yàn)室，江蘇 南京 210098； 2.河海大學(xué)環(huán)境學(xué)院，江蘇 南京 210098)

介紹了水體中氟西汀的來(lái)源及歸趨，闡述了該物質(zhì)在不同水環(huán)境介質(zhì)中的賦存狀態(tài)，以及其在水生生物體內(nèi)的累積規(guī)律和不同的生態(tài)毒理效應(yīng)。最后，基于目前的研究現(xiàn)狀提出了未來(lái)氟西汀研究中亟待解決的關(guān)鍵問(wèn)題。

氟西?。凰鷳B(tài)環(huán)境安全；賦存；累積；生物效應(yīng)

近年來(lái)，隨著現(xiàn)代社會(huì)生活節(jié)奏的加快和競(jìng)爭(zhēng)的白熱化，患有精神抑郁的人群明顯增多，目前我國(guó)的抑郁癥患者預(yù)估高達(dá)9 000萬(wàn)人，導(dǎo)致抗抑郁類(lèi)藥物的使用大量增加[1]。在這些抗抑郁藥物中，氟西汀(Fluoxetine，F(xiàn)LX)作為一種選擇性5-羥色胺再攝取抑制劑，可以通過(guò)選擇性抑制神經(jīng)突觸細(xì)胞對(duì)神經(jīng)系統(tǒng)突觸前釋放的血清素再吸收，而增加細(xì)胞外可以和突觸后受體結(jié)合的血清素水平來(lái)實(shí)現(xiàn)抗抑郁效果[2]。FLX作為目前臨床上治療抑郁癥的首選藥物之一，已在許多國(guó)家和地區(qū)得以廣泛應(yīng)用。隨著使用量的不斷增加，F(xiàn)LX也不可避免地在其制造和使用過(guò)程中通過(guò)各種途徑進(jìn)入水體，進(jìn)而賦存于水體、沉積物以及水生生物體等不同介質(zhì)中[3-4]。同時(shí)，由于FLX的特殊生物活性，能夠通過(guò)作用于水生生物體的中樞神經(jīng)系統(tǒng)，干擾神經(jīng)內(nèi)分泌信號(hào)，從而威脅生物體個(gè)體的生長(zhǎng)和種群的繁衍，給水生態(tài)環(huán)境安全甚至人類(lèi)健康帶來(lái)潛在風(fēng)險(xiǎn)，并因此逐步成為水體最需關(guān)注的藥物污染物之一[5-6]。

1 來(lái)源和歸趨

水環(huán)境中FLX的來(lái)源相對(duì)廣泛，主要為市政污水處理廠尾水。FLX經(jīng)患者口服攝入后，有20%～30%未經(jīng)人體代謝直接隨著尿液或糞便排出體外，進(jìn)入市政管網(wǎng)，并經(jīng)污水處理廠處理后隨尾水排入天然水體[7]。但是，現(xiàn)有的污水處理工藝很難將FLX完全去除，甚至一部分工藝對(duì)FLX幾乎沒(méi)有處理效果，從而使FLX直接進(jìn)入天然水體[8-10]。例如，MacLeod等[10]發(fā)現(xiàn)采用活性污泥法的污水處理廠對(duì)FLX的去除率不足8%，污水處理廠成為受納水體中FLX污染的最主要來(lái)源。此外，污水處理廠甚至可以將FLX的代謝產(chǎn)物諾氟西汀(Norfluoxetine，NFLX)再次轉(zhuǎn)化為母體FLX，從而再次增加水體中FLX的濃度[11]。醫(yī)院或醫(yī)藥企業(yè)的污水排放也是水體中FLX的一大來(lái)源，但相較于污水處理廠尾水排放，醫(yī)藥廢水對(duì)水體中FLX的貢獻(xiàn)率不足1%[12-13]。此外，過(guò)期或未經(jīng)使用的FLX作為生活垃圾隨意丟棄也是其進(jìn)入水體的可能途徑之一[4]。

水環(huán)境中的FLX一部分在光照、微生物等作用下得以降解，另一部分則能夠通過(guò)水-沉積物間的遷移轉(zhuǎn)化進(jìn)入沉積物中，甚至通過(guò)沉積物的解吸附過(guò)程重新進(jìn)入水體[4]。此外，F(xiàn)LX也會(huì)累積于水生生物，尤其是高營(yíng)養(yǎng)級(jí)的水生動(dòng)物體內(nèi)，如魚(yú)類(lèi)、無(wú)脊椎動(dòng)物等，通過(guò)食物鏈進(jìn)行傳遞，并產(chǎn)生生物放大效應(yīng)[14-15]。

2 水環(huán)境介質(zhì)中的賦存

自Weston等[17]首次報(bào)道了污水廠尾水存在FLX污染后，世界范圍內(nèi)的研究人員開(kāi)始高度關(guān)注這一精神類(lèi)藥物在水體中的殘留。伴隨著化學(xué)檢測(cè)技術(shù)的不斷提高，美國(guó)、加拿大、西班牙以及亞洲一些國(guó)家和地區(qū)的水體環(huán)境中相繼檢測(cè)到了FLX的存在，其質(zhì)量濃度水平一般在ng/L至μg/L級(jí)別，見(jiàn)表1。檢出的水體也從污水廠的進(jìn)、出水發(fā)展到地表水和地下水，甚至飲用水。和水體常見(jiàn)的其他藥物污染物相比，F(xiàn)LX的檢出率變化較大。美國(guó)地質(zhì)調(diào)查局對(duì)全美139條河流的檢測(cè)結(jié)果顯示，F(xiàn)LX的檢出率僅有1.2%，且大多集中于污水廠受納水體中[18]。但是，F(xiàn)errer等[19]對(duì)美國(guó)不同水體的污染物檢測(cè)顯示，有25%的水樣中檢測(cè)出FLX的存在。我國(guó)洞庭湖水域的FLX檢出率更是高達(dá)55%，尤其是東洞庭湖水域更是100%檢出[20]。相較于淡水環(huán)境，關(guān)于FLX在海洋水體中賦存的報(bào)道較為罕見(jiàn)，僅有Pait等[21]在美國(guó)切薩皮克海灣的南部檢測(cè)出FLX的存在，質(zhì)量濃度為3 ng/L。

除水體環(huán)境外，F(xiàn)LX也能夠通過(guò)水-沉積物界面遷移到沉積物中，然而，目前關(guān)于FLX在沉積物中賦存的報(bào)道相對(duì)較少。Schultz等[7]在美國(guó)科羅拉多博爾德河底泥中檢測(cè)出FLX的質(zhì)量濃度范圍為0.39～19.37 ng/g。Bringolf等[37]檢測(cè)了美國(guó)紐斯河支流某污水處理廠出水口、出水口下游50 m、100 m 處河流底泥中FLX的濃度，結(jié)果顯示3個(gè)采樣點(diǎn)采集的底泥中的檢出濃度分別為17.4 ng/g、5.3 ng/g、1.3 ng/g，表現(xiàn)為FLX沿河流流向不斷衰減。這表明河流底泥中的FLX主要來(lái)源于污水處理廠的尾水排放，且其濃度與距污水處理廠排污口的河流長(zhǎng)度存在負(fù)相關(guān)性。但相較于河流底泥，污水處理廠污泥中FLX的檢出濃度更高，最高達(dá)到了μg/g級(jí)別，這主要?dú)w因于FLX在污水中的濃度遠(yuǎn)大于天然水體，沉積物中的FLX主要來(lái)源于水體污染物的遷移和蓄積。如Vasskog等[44]報(bào)道了挪威兩家污水處理廠污泥中FLX的賦存狀況，檢出其濃度在30～40 ng/g；Radjenovic等[45]在某污水處理廠的處理污泥中檢出的FLX濃度為174.1 ng/g；而Lajeunesse等[32]報(bào)道了加拿大某5家污水處理廠處理污泥中不同抗抑郁藥的含量，其中FLX的最高檢出濃度甚至達(dá)到了1 033 ng/g。

表1 不同地區(qū)水體中FLX的檢出濃度

3 代謝轉(zhuǎn)化和生物累積

FLX被人體攝入后，其代謝路徑為肝臟代謝，并以N-去甲基和葡萄酸鹽的形式排出體外，但代謝程度存在個(gè)體差異性[46]。與之相類(lèi)似，F(xiàn)LX被水生生物體攝入后，主要的代謝產(chǎn)物為NFLX，其生物活性甚至比母體化合物FLX更強(qiáng)效[47]。由于FLX和NFLX都具有較高的辛醇水分配系數(shù)，兩者在被水生生物體攝取后都極易蓄積于體內(nèi)，尤其是在高營(yíng)養(yǎng)級(jí)的硬骨魚(yú)類(lèi)體內(nèi)。Brooks等[14]首先報(bào)道了美國(guó)野生魚(yú)類(lèi)組織中FLX和NFLX的賦存和累積，并發(fā)現(xiàn)兩者在肝臟和腦組織中的水平最高，肌肉最低。這一發(fā)現(xiàn)和Ramirez等[48]的研究結(jié)果相類(lèi)似，這可能和肝臟是FLX在魚(yú)體內(nèi)的主要代謝器官，而腦組織則是FLX的主要靶標(biāo)器官有關(guān)。其后，大量關(guān)于野生魚(yú)類(lèi)組織內(nèi)FLX和NFLX的累積也相繼被報(bào)道出來(lái)，具體情況見(jiàn)表2。

相較于野外檢測(cè)，實(shí)驗(yàn)室內(nèi)關(guān)于FLX的生物累積和代謝研究開(kāi)展相對(duì)較晚，但內(nèi)容更為系統(tǒng)和具體。Paterson等[49]發(fā)現(xiàn)日本青鳉在暴露于0.64 μg/L的FLX溶液7 d后就累積了大量的FLX及其代謝產(chǎn)物NFLX，質(zhì)量比分別為40.8 μg/kg和64.3 μg/kg，這表明FLX在7 d內(nèi)就可以大量代謝為NFLX，且NFLX呈現(xiàn)出更高的累積潛能。這一結(jié)果也得到Gelsleichter等[50]的證實(shí)，他們認(rèn)為與FLX相比，NFLX具有更小的極性，因此更易于富集在魚(yú)體組織內(nèi)，進(jìn)而造成相同甚至更壞的生態(tài)影響。Chu等[51]同樣發(fā)現(xiàn)，隨著暴露時(shí)間的增加，代謝物NFLX在魚(yú)體組織的累積水平會(huì)逐步和FLX相持平甚至更高。但需要特別關(guān)注的是，F(xiàn)LX作為一種弱堿性藥物化合物，其在較高pH值環(huán)境下主要以中性分子形態(tài)存在，在低pH環(huán)境下則以離子形態(tài)為主要存在形式，而化合物的離子化會(huì)顯著影響其在生物膜上的轉(zhuǎn)運(yùn)過(guò)程，并最終影響其在水生生物的累積水平[52]?？梢?jiàn)，水體不同pH值環(huán)境可能會(huì)顯著影響FLX在生物體內(nèi)的累積?；诖?，Nakamura等[52]研究了不同的pH暴露條件下FLX在日本青鳉體內(nèi)的富集情況，結(jié)果顯示在pH值為7、8和9的條件下，F(xiàn)LX及其代謝產(chǎn)物NFLX的生物累積系數(shù)(bioconcentration factor，BCF)分別為13、37和330以及100、170和720，水體pH值越靠近FLX的離子平衡常數(shù)，其越容易富集于生物體中。因此，水體的pH值會(huì)影響FLX在魚(yú)體內(nèi)的累積水平，進(jìn)而改變其組織分布和毒性大小，所以?xún)H僅從辛醇水分配系數(shù)來(lái)評(píng)估藥物等活性化合物在生物體的累積還存在一定的不足，需要更多的研究加以論證。

除魚(yú)類(lèi)外，F(xiàn)LX在其他水生生物體內(nèi)的累積也時(shí)有報(bào)道。Bringolf等[37]發(fā)現(xiàn)美國(guó)紐斯河支流中的貽貝(Elliptiocomplanata)體內(nèi)即有FLX的累積，生物累積因子(bioaccumulation factor，BAF)達(dá)到125～1 347。在實(shí)驗(yàn)室研究中，F(xiàn)arrzellitti等[15]將紫貽貝(Mytilusgalloprovincialis)暴露于FLX溶液7 d后發(fā)現(xiàn)，F(xiàn)LX在紫貽貝的BCF介于200～800；Silva等[47]則發(fā)現(xiàn)紫貽貝暴露于75 ng/L的FLX溶液3 d后，70%的樣品中都檢測(cè)出了FLX的存在，10%的樣品中檢測(cè)出NFLX，當(dāng)暴露達(dá)到15 d后，F(xiàn)LX和NFLX的檢出率全部達(dá)到100%，平均累積質(zhì)量比也分別達(dá)到9.31 ng/g和11.65 ng/g，這表明隨著暴露時(shí)間的增加，生物體內(nèi)富集的FLX可能逐漸代謝為NFLX。Gust等[53]也發(fā)現(xiàn)FLX可以在田螺(Potamopyrgusantipodarum)和盤(pán)螺(Valvatapiscinalis)體內(nèi)產(chǎn)生累積并逐漸代謝為NFLX，但NFLX的BCF遠(yuǎn)小于FLX。

表2 FLX和NFLX在野生魚(yú)類(lèi)體內(nèi)的富集濃度

4 生態(tài)毒理效應(yīng)

隨著FLX使用量的不斷增加，其對(duì)人體的副作用也不斷被披露，包括胃腸道功能紊亂、厭食、精神異常、性功能障礙、精子活性降低等。當(dāng)這類(lèi)物質(zhì)進(jìn)入水體和生物體后，其也可能通過(guò)調(diào)控和模仿神經(jīng)遞質(zhì)5-羥色胺的作用，激活暴露生物體內(nèi)轉(zhuǎn)運(yùn)蛋白和受體的調(diào)節(jié)機(jī)制，最終對(duì)各類(lèi)水生非靶標(biāo)生物產(chǎn)生較為嚴(yán)重的負(fù)面效應(yīng)[55-56]。自Brooks等[57]首先報(bào)道了賦存于水體和沉積物中的FLX可能會(huì)對(duì)魚(yú)類(lèi)產(chǎn)生多種不良影響以后，大量研究人員開(kāi)始關(guān)注水體中FLX的生態(tài)毒理效應(yīng)。其后《Science》發(fā)表了《Fish on Prozac》的報(bào)道，環(huán)境中殘留的FLX對(duì)生物體的潛在危害性開(kāi)始進(jìn)入公眾視野。作為一種精神類(lèi)藥物，F(xiàn)LX對(duì)水生生物的影響主要體現(xiàn)在神經(jīng)功能和行為學(xué)損傷。已有研究發(fā)現(xiàn)，水體FLX污染明顯阻礙了魚(yú)類(lèi)的游動(dòng)，表現(xiàn)出行動(dòng)障礙，覓食和逃避天敵行為遲緩，求偶和交配行為受抑制等[58-62]。Abreu等[63]發(fā)現(xiàn)環(huán)境相關(guān)濃度的FLX可以直接抑制斑馬魚(yú)體內(nèi)皮質(zhì)醇激素的合成，從而引起魚(yú)體應(yīng)急響應(yīng)行為遲緩。同時(shí)，F(xiàn)LX還可以通過(guò)下調(diào)斑馬魚(yú)腦內(nèi)神經(jīng)葉激素、尿皮素和泌乳素等相關(guān)神經(jīng)肽的表達(dá)而減緩魚(yú)體的焦慮行為[64]。Dzieweczynski等[65]進(jìn)一步研究發(fā)現(xiàn)FLX還可以顯著降低雄性暹羅斗魚(yú)(Bettasplendens)的冒險(xiǎn)行為，呈現(xiàn)濃度相關(guān)性且極有可能影響個(gè)體的生存。除了抑制逃避捕食行為外，Pelli等[66]還證實(shí)環(huán)境相當(dāng)濃度的FLX可能會(huì)干擾生物體能量代謝過(guò)程而抑制古比魚(yú)(Poeciliareticulata)的生長(zhǎng)發(fā)育。已有研究證實(shí)，F(xiàn)LX的存在可以引起魚(yú)體厭食等癥狀，并通過(guò)磷酸腺苷活化的蛋白激酶路徑促進(jìn)生物體內(nèi)葡萄糖、脂肪和氨基酸的代謝，進(jìn)而減緩魚(yú)體內(nèi)的能量存儲(chǔ)，干擾其正常的生長(zhǎng)發(fā)育[67-69]。除魚(yú)體外，水體FLX暴露也會(huì)顯著降低小龍蝦(Orconectesrusticus)[70]和蝌蚪(Anaximperator)[71]的移動(dòng)能力和逃避天敵能力，從而削弱它們的生存能力。

考慮到水生生物，特別是魚(yú)類(lèi)的生殖行為(性腺成熟、求偶等)受到其體內(nèi)血清素的調(diào)節(jié)，水體中FLX這一血清素抑制劑的存在很可能會(huì)影響到水生生物的繁殖過(guò)程[72-73]。Mennigen等[74]發(fā)現(xiàn)FLX可以通過(guò)減緩雄魚(yú)精子釋放、降低睪丸素水平以及抑制性信息素合成等多個(gè)路徑干擾雄性金魚(yú)的生殖軸線(xiàn)，進(jìn)而降低其生殖能力。Bringolf等[37]也認(rèn)為FLX會(huì)促使雌性貽貝分娩出無(wú)法生存的幼蟲(chóng)并誘導(dǎo)雄性貽貝釋放精子，從而對(duì)淡水貽貝的種群繁殖產(chǎn)生消極影響。即使痕量水平的FLX在長(zhǎng)時(shí)間暴露后同樣會(huì)導(dǎo)致貽貝出現(xiàn)個(gè)體生長(zhǎng)受阻和性腺指數(shù)降低等情況，從而影響到種群的繁衍[75]。與之相反，Campos等[76]證實(shí)FLX的加入可以激活大型蚤腦內(nèi)血清素的免疫活性，從而改變實(shí)際環(huán)境中低食物量導(dǎo)致的大型蚤繁殖效率低下等狀況，明顯增加了子代的數(shù)量，但其個(gè)體相對(duì)較小。這表明FLX對(duì)生物體繁殖的影響并不是一成不變的，生物種類(lèi)和環(huán)境條件都可能會(huì)改變這些影響。

此外，水生生物體的代謝功能、抗氧化體系和內(nèi)分泌系統(tǒng)等方面也受FLX的影響。相關(guān)體外實(shí)驗(yàn)表明，F(xiàn)LX能夠明顯抑制魚(yú)類(lèi)肝臟內(nèi)I相代謝酶系細(xì)胞色素P450的活性(如CYP1s、CYP2K和CYP3A等)[77-80]，表現(xiàn)為廣譜CYP系列酶系抑制劑，從而影響?hù)~(yú)體對(duì)外源性污染物的清除效率。而這一代謝抑制效應(yīng)可能會(huì)促進(jìn)共存污染物羅紅霉素、普羅奈爾、炔雌醇等在生物體內(nèi)的蓄積，并導(dǎo)致了更為明顯的生物損傷[81-83]。此外，Zhang等[84]認(rèn)為FLX還可以通過(guò)抑制P糖蛋白(P-glycoprotein，Pgp，0相代謝)和谷胱甘肽轉(zhuǎn)化酶(Glutathione S-Transferase，GST，II相代謝)等路徑削弱生物體的代謝功能，進(jìn)而增加共存污染物對(duì)生物體內(nèi)的危害。除了代謝功能外，F(xiàn)LX也會(huì)顯著破壞水生生物的抗氧化酶體系，引發(fā)氧化應(yīng)激反應(yīng)，增加生物體氧化損傷的風(fēng)險(xiǎn)[85-86]。例如，Ding等[81]研究發(fā)現(xiàn)FLX暴露會(huì)顯著抑制鯽魚(yú)(Carassiusaurassius)肝臟內(nèi)超氧化物歧化酶(superoxide dismutase，SOD)活性以及增加鯽魚(yú)肝臟丙二醛(malonaldehyde，MDA)濃度，且呈現(xiàn)明顯的濃度效應(yīng)關(guān)系。Cunha等[87]也證實(shí)FLX可以明顯降低斑馬魚(yú)幼魚(yú)體內(nèi)的SOD活性，進(jìn)而減弱體內(nèi)氧化自由基(如過(guò)氧化氫)的代謝和清除，干擾其正常的發(fā)育過(guò)程。Abreu等[2]甚至發(fā)現(xiàn)這一增加的氧化損傷可能會(huì)導(dǎo)致斑馬魚(yú)體內(nèi)滲透壓調(diào)節(jié)功能的失調(diào)。與氧化代謝功能相比較，F(xiàn)LX對(duì)生物體內(nèi)分泌功能干擾的報(bào)道更為少見(jiàn)，主要集中在對(duì)內(nèi)循環(huán)物質(zhì)的影響上。例如，Hazelton等[88]發(fā)現(xiàn)200 ng/L的FLX明顯誘導(dǎo)了斑馬貝(Dreissenapolymorpha)內(nèi)循環(huán)雌二醇的水平，而Schultz等[89]甚至發(fā)現(xiàn)了FLX可以誘導(dǎo)雄性黑頭呆魚(yú)體內(nèi)合成卵黃蛋白原，表現(xiàn)出強(qiáng)烈的雌激素效應(yīng)?？傊?，水體FLX污染可能會(huì)對(duì)水生生物產(chǎn)生神經(jīng)毒性并干擾其氧化代謝和內(nèi)分泌功能，從而對(duì)其應(yīng)激性、覓食和行為產(chǎn)生影響，最終威脅到個(gè)體的生長(zhǎng)繁殖和種群的延續(xù)。

5 展 望

a. 需要考察FLX在不同水環(huán)境介質(zhì)中的遷移轉(zhuǎn)化規(guī)律，知曉FLX在水-沉積物-生物體之間的分配行為以及在不同介質(zhì)中的降解過(guò)程。

b. 加強(qiáng)FLX代謝產(chǎn)物理化性質(zhì)和生態(tài)毒性的研究，并考察水質(zhì)因素(pH、溶解性有機(jī)質(zhì)、離子強(qiáng)度、溫度等)及水動(dòng)力變化對(duì)FLX及代謝產(chǎn)物生物累積和生物效應(yīng)的影響，從而建立水質(zhì)和水動(dòng)力學(xué)模型綜合分析不同水環(huán)境FLX污染的生態(tài)風(fēng)險(xiǎn)。

c. 結(jié)合水生態(tài)系統(tǒng)的食物鏈結(jié)構(gòu)，研究水環(huán)境中FLX在食物鏈不同營(yíng)養(yǎng)級(jí)生物間的傳遞和代謝轉(zhuǎn)化過(guò)程。建立從種群、個(gè)體、器官組織、細(xì)胞到基因的不同水平的毒理學(xué)指標(biāo)體系，全面掌握FLX對(duì)生態(tài)系統(tǒng)及人體健康的潛在危害，最終建立起FLX污染的生態(tài)風(fēng)險(xiǎn)評(píng)價(jià)體系。

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Advancesinstudiesonoccurrence,accumulationandbiologicaleffectsofFluoxetineinwater

YANZhenhua1,2,SUNHongwei1,2,LUGuanghua1,2

(1.KeyLaboratoryofIntegratedRegulationandResourceDevelopmentonShallowLakesofMinistryofEducation,HohaiUniversity,Nanjing210098,China； 2.CollegeofEnvironment,HohaiUniversity,Nanjing210098,China)

In this study, the sources and fates of Fluoxetine in the aquatic environment were firstly introduced. And then, the occurrence state of this substance in different water environment medium was elaborated. Besides, its accumulation law in aquatic organisms and different ecotoxicological effects were studied as well. Finally, based on the current research status, the key problems to be solved in the future Fluoxetine research were put forward.

Fluoxetine; water ecological environment security; occurrence; accumulation; biological effect

10.3880/j.issn.1004-6933.2017.06.23

國(guó)家自然科學(xué)基金(51509071)；江蘇省自然科學(xué)基金(BK20150801)

閆振華(1987—)，男，講師，博士，主要從事水體復(fù)合污染等研究。E-mail:hwahuer@hhu.edu.cn

陸光華，教授。E-mail:ghlu@hhu.edu.cn

X522

A

1004-6933(2017)06-0147-08

2017-04-17 編輯：王 芳)