水体中氟西汀的赋存、累积和生物效应研究进展

闫振华，孙红伟，陆光华

(1.河海大学浅水湖泊综合治理与资源开发教育部重点实验室，江苏 南京 210098； 2.河海大学环境学院，江苏 南京 210098)

水体中氟西汀的赋存、累积和生物效应研究进展

闫振华1,2，孙红伟1,2，陆光华1,2

(1.河海大学浅水湖泊综合治理与资源开发教育部重点实验室，江苏 南京 210098； 2.河海大学环境学院，江苏 南京 210098)

介绍了水体中氟西汀的来源及归趋，阐述了该物质在不同水环境介质中的赋存状态，以及其在水生生物体内的累积规律和不同的生态毒理效应。最后，基于目前的研究现状提出了未来氟西汀研究中亟待解决的关键问题。

氟西汀；水生态环境安全；赋存；累积；生物效应

近年来，随着现代社会生活节奏的加快和竞争的白热化，患有精神抑郁的人群明显增多，目前我国的抑郁症患者预估高达9 000万人，导致抗抑郁类药物的使用大量增加[1]。在这些抗抑郁药物中，氟西汀(Fluoxetine，FLX)作为一种选择性5-羟色胺再摄取抑制剂，可以通过选择性抑制神经突触细胞对神经系统突触前释放的血清素再吸收，而增加细胞外可以和突触后受体结合的血清素水平来实现抗抑郁效果[2]。FLX作为目前临床上治疗抑郁症的首选药物之一，已在许多国家和地区得以广泛应用。随着使用量的不断增加，FLX也不可避免地在其制造和使用过程中通过各种途径进入水体，进而赋存于水体、沉积物以及水生生物体等不同介质中[3-4]。同时，由于FLX的特殊生物活性，能够通过作用于水生生物体的中枢神经系统，干扰神经内分泌信号，从而威胁生物体个体的生长和种群的繁衍，给水生态环境安全甚至人类健康带来潜在风险，并因此逐步成为水体最需关注的药物污染物之一[5-6]。

1 来源和归趋

水环境中FLX的来源相对广泛，主要为市政污水处理厂尾水。FLX经患者口服摄入后，有20%～30%未经人体代谢直接随着尿液或粪便排出体外，进入市政管网，并经污水处理厂处理后随尾水排入天然水体[7]。但是，现有的污水处理工艺很难将FLX完全去除，甚至一部分工艺对FLX几乎没有处理效果，从而使FLX直接进入天然水体[8-10]。例如，MacLeod等[10]发现采用活性污泥法的污水处理厂对FLX的去除率不足8%，污水处理厂成为受纳水体中FLX污染的最主要来源。此外，污水处理厂甚至可以将FLX的代谢产物诺氟西汀(Norfluoxetine，NFLX)再次转化为母体FLX，从而再次增加水体中FLX的浓度[11]。医院或医药企业的污水排放也是水体中FLX的一大来源，但相较于污水处理厂尾水排放，医药废水对水体中FLX的贡献率不足1%[12-13]。此外，过期或未经使用的FLX作为生活垃圾随意丢弃也是其进入水体的可能途径之一[4]。

水环境中的FLX一部分在光照、微生物等作用下得以降解，另一部分则能够通过水-沉积物间的迁移转化进入沉积物中，甚至通过沉积物的解吸附过程重新进入水体[4]。此外，FLX也会累积于水生生物，尤其是高营养级的水生动物体内，如鱼类、无脊椎动物等，通过食物链进行传递，并产生生物放大效应[14-15]。

2 水环境介质中的赋存

自Weston等[17]首次报道了污水厂尾水存在FLX污染后，世界范围内的研究人员开始高度关注这一精神类药物在水体中的残留。伴随着化学检测技术的不断提高，美国、加拿大、西班牙以及亚洲一些国家和地区的水体环境中相继检测到了FLX的存在，其质量浓度水平一般在ng/L至μg/L级别，见表1。检出的水体也从污水厂的进、出水发展到地表水和地下水，甚至饮用水。和水体常见的其他药物污染物相比，FLX的检出率变化较大。美国地质调查局对全美139条河流的检测结果显示，FLX的检出率仅有1.2%，且大多集中于污水厂受纳水体中[18]。但是，Ferrer等[19]对美国不同水体的污染物检测显示，有25%的水样中检测出FLX的存在。我国洞庭湖水域的FLX检出率更是高达55%，尤其是东洞庭湖水域更是100%检出[20]。相较于淡水环境，关于FLX在海洋水体中赋存的报道较为罕见，仅有Pait等[21]在美国切萨皮克海湾的南部检测出FLX的存在，质量浓度为3 ng/L。

除水体环境外，FLX也能够通过水-沉积物界面迁移到沉积物中，然而，目前关于FLX在沉积物中赋存的报道相对较少。Schultz等[7]在美国科罗拉多博尔德河底泥中检测出FLX的质量浓度范围为0.39～19.37 ng/g。Bringolf等[37]检测了美国纽斯河支流某污水处理厂出水口、出水口下游50 m、100 m 处河流底泥中FLX的浓度，结果显示3个采样点采集的底泥中的检出浓度分别为17.4 ng/g、5.3 ng/g、1.3 ng/g，表现为FLX沿河流流向不断衰减。这表明河流底泥中的FLX主要来源于污水处理厂的尾水排放，且其浓度与距污水处理厂排污口的河流长度存在负相关性。但相较于河流底泥，污水处理厂污泥中FLX的检出浓度更高，最高达到了μg/g级别，这主要归因于FLX在污水中的浓度远大于天然水体，沉积物中的FLX主要来源于水体污染物的迁移和蓄积。如Vasskog等[44]报道了挪威两家污水处理厂污泥中FLX的赋存状况，检出其浓度在30～40 ng/g；Radjenovic等[45]在某污水处理厂的处理污泥中检出的FLX浓度为174.1 ng/g；而Lajeunesse等[32]报道了加拿大某5家污水处理厂处理污泥中不同抗抑郁药的含量，其中FLX的最高检出浓度甚至达到了1 033 ng/g。

表1 不同地区水体中FLX的检出浓度

3 代谢转化和生物累积

FLX被人体摄入后，其代谢路径为肝脏代谢，并以N-去甲基和葡萄酸盐的形式排出体外，但代谢程度存在个体差异性[46]。与之相类似，FLX被水生生物体摄入后，主要的代谢产物为NFLX，其生物活性甚至比母体化合物FLX更强效[47]。由于FLX和NFLX都具有较高的辛醇水分配系数，两者在被水生生物体摄取后都极易蓄积于体内，尤其是在高营养级的硬骨鱼类体内。Brooks等[14]首先报道了美国野生鱼类组织中FLX和NFLX的赋存和累积，并发现两者在肝脏和脑组织中的水平最高，肌肉最低。这一发现和Ramirez等[48]的研究结果相类似，这可能和肝脏是FLX在鱼体内的主要代谢器官，而脑组织则是FLX的主要靶标器官有关。其后，大量关于野生鱼类组织内FLX和NFLX的累积也相继被报道出来，具体情况见表2。

相较于野外检测，实验室内关于FLX的生物累积和代谢研究开展相对较晚，但内容更为系统和具体。Paterson等[49]发现日本青鳉在暴露于0.64 μg/L的FLX溶液7 d后就累积了大量的FLX及其代谢产物NFLX，质量比分别为40.8 μg/kg和64.3 μg/kg，这表明FLX在7 d内就可以大量代谢为NFLX，且NFLX呈现出更高的累积潜能。这一结果也得到Gelsleichter等[50]的证实，他们认为与FLX相比，NFLX具有更小的极性，因此更易于富集在鱼体组织内，进而造成相同甚至更坏的生态影响。Chu等[51]同样发现，随着暴露时间的增加，代谢物NFLX在鱼体组织的累积水平会逐步和FLX相持平甚至更高。但需要特别关注的是，FLX作为一种弱碱性药物化合物，其在较高pH值环境下主要以中性分子形态存在，在低pH环境下则以离子形态为主要存在形式，而化合物的离子化会显著影响其在生物膜上的转运过程，并最终影响其在水生生物的累积水平[52]。可见，水体不同pH值环境可能会显著影响FLX在生物体内的累积。基于此，Nakamura等[52]研究了不同的pH暴露条件下FLX在日本青鳉体内的富集情况，结果显示在pH值为7、8和9的条件下，FLX及其代谢产物NFLX的生物累积系数(bioconcentration factor，BCF)分别为13、37和330以及100、170和720，水体pH值越靠近FLX的离子平衡常数，其越容易富集于生物体中。因此，水体的pH值会影响FLX在鱼体内的累积水平，进而改变其组织分布和毒性大小，所以仅仅从辛醇水分配系数来评估药物等活性化合物在生物体的累积还存在一定的不足，需要更多的研究加以论证。

除鱼类外，FLX在其他水生生物体内的累积也时有报道。Bringolf等[37]发现美国纽斯河支流中的贻贝(Elliptiocomplanata)体内即有FLX的累积，生物累积因子(bioaccumulation factor，BAF)达到125～1 347。在实验室研究中，Farrzellitti等[15]将紫贻贝(Mytilusgalloprovincialis)暴露于FLX溶液7 d后发现，FLX在紫贻贝的BCF介于200～800；Silva等[47]则发现紫贻贝暴露于75 ng/L的FLX溶液3 d后，70%的样品中都检测出了FLX的存在，10%的样品中检测出NFLX，当暴露达到15 d后，FLX和NFLX的检出率全部达到100%，平均累积质量比也分别达到9.31 ng/g和11.65 ng/g，这表明随着暴露时间的增加，生物体内富集的FLX可能逐渐代谢为NFLX。Gust等[53]也发现FLX可以在田螺(Potamopyrgusantipodarum)和盘螺(Valvatapiscinalis)体内产生累积并逐渐代谢为NFLX，但NFLX的BCF远小于FLX。

表2 FLX和NFLX在野生鱼类体内的富集浓度

4 生态毒理效应

随着FLX使用量的不断增加，其对人体的副作用也不断被披露，包括胃肠道功能紊乱、厌食、精神异常、性功能障碍、精子活性降低等。当这类物质进入水体和生物体后，其也可能通过调控和模仿神经递质5-羟色胺的作用，激活暴露生物体内转运蛋白和受体的调节机制，最终对各类水生非靶标生物产生较为严重的负面效应[55-56]。自Brooks等[57]首先报道了赋存于水体和沉积物中的FLX可能会对鱼类产生多种不良影响以后，大量研究人员开始关注水体中FLX的生态毒理效应。其后《Science》发表了《Fish on Prozac》的报道，环境中残留的FLX对生物体的潜在危害性开始进入公众视野。作为一种精神类药物，FLX对水生生物的影响主要体现在神经功能和行为学损伤。已有研究发现，水体FLX污染明显阻碍了鱼类的游动，表现出行动障碍，觅食和逃避天敌行为迟缓，求偶和交配行为受抑制等[58-62]。Abreu等[63]发现环境相关浓度的FLX可以直接抑制斑马鱼体内皮质醇激素的合成，从而引起鱼体应急响应行为迟缓。同时，FLX还可以通过下调斑马鱼脑内神经叶激素、尿皮素和泌乳素等相关神经肽的表达而减缓鱼体的焦虑行为[64]。Dzieweczynski等[65]进一步研究发现FLX还可以显著降低雄性暹罗斗鱼(Bettasplendens)的冒险行为，呈现浓度相关性且极有可能影响个体的生存。除了抑制逃避捕食行为外，Pelli等[66]还证实环境相当浓度的FLX可能会干扰生物体能量代谢过程而抑制古比鱼(Poeciliareticulata)的生长发育。已有研究证实，FLX的存在可以引起鱼体厌食等症状，并通过磷酸腺苷活化的蛋白激酶路径促进生物体内葡萄糖、脂肪和氨基酸的代谢，进而减缓鱼体内的能量存储，干扰其正常的生长发育[67-69]。除鱼体外，水体FLX暴露也会显著降低小龙虾(Orconectesrusticus)[70]和蝌蚪(Anaximperator)[71]的移动能力和逃避天敌能力，从而削弱它们的生存能力。

考虑到水生生物，特别是鱼类的生殖行为(性腺成熟、求偶等)受到其体内血清素的调节，水体中FLX这一血清素抑制剂的存在很可能会影响到水生生物的繁殖过程[72-73]。Mennigen等[74]发现FLX可以通过减缓雄鱼精子释放、降低睾丸素水平以及抑制性信息素合成等多个路径干扰雄性金鱼的生殖轴线，进而降低其生殖能力。Bringolf等[37]也认为FLX会促使雌性贻贝分娩出无法生存的幼虫并诱导雄性贻贝释放精子，从而对淡水贻贝的种群繁殖产生消极影响。即使痕量水平的FLX在长时间暴露后同样会导致贻贝出现个体生长受阻和性腺指数降低等情况，从而影响到种群的繁衍[75]。与之相反，Campos等[76]证实FLX的加入可以激活大型蚤脑内血清素的免疫活性，从而改变实际环境中低食物量导致的大型蚤繁殖效率低下等状况，明显增加了子代的数量，但其个体相对较小。这表明FLX对生物体繁殖的影响并不是一成不变的，生物种类和环境条件都可能会改变这些影响。

此外，水生生物体的代谢功能、抗氧化体系和内分泌系统等方面也受FLX的影响。相关体外实验表明，FLX能够明显抑制鱼类肝脏内I相代谢酶系细胞色素P450的活性(如CYP1s、CYP2K和CYP3A等)[77-80]，表现为广谱CYP系列酶系抑制剂，从而影响鱼体对外源性污染物的清除效率。而这一代谢抑制效应可能会促进共存污染物罗红霉素、普罗奈尔、炔雌醇等在生物体内的蓄积，并导致了更为明显的生物损伤[81-83]。此外，Zhang等[84]认为FLX还可以通过抑制P糖蛋白(P-glycoprotein，Pgp，0相代谢)和谷胱甘肽转化酶(Glutathione S-Transferase，GST，II相代谢)等路径削弱生物体的代谢功能，进而增加共存污染物对生物体内的危害。除了代谢功能外，FLX也会显著破坏水生生物的抗氧化酶体系，引发氧化应激反应，增加生物体氧化损伤的风险[85-86]。例如，Ding等[81]研究发现FLX暴露会显著抑制鲫鱼(Carassiusaurassius)肝脏内超氧化物歧化酶(superoxide dismutase，SOD)活性以及增加鲫鱼肝脏丙二醛(malonaldehyde，MDA)浓度，且呈现明显的浓度效应关系。Cunha等[87]也证实FLX可以明显降低斑马鱼幼鱼体内的SOD活性，进而减弱体内氧化自由基(如过氧化氢)的代谢和清除，干扰其正常的发育过程。Abreu等[2]甚至发现这一增加的氧化损伤可能会导致斑马鱼体内渗透压调节功能的失调。与氧化代谢功能相比较，FLX对生物体内分泌功能干扰的报道更为少见，主要集中在对内循环物质的影响上。例如，Hazelton等[88]发现200 ng/L的FLX明显诱导了斑马贝(Dreissenapolymorpha)内循环雌二醇的水平，而Schultz等[89]甚至发现了FLX可以诱导雄性黑头呆鱼体内合成卵黄蛋白原，表现出强烈的雌激素效应。总之，水体FLX污染可能会对水生生物产生神经毒性并干扰其氧化代谢和内分泌功能，从而对其应激性、觅食和行为产生影响，最终威胁到个体的生长繁殖和种群的延续。

5 展 望

a. 需要考察FLX在不同水环境介质中的迁移转化规律，知晓FLX在水-沉积物-生物体之间的分配行为以及在不同介质中的降解过程。

b. 加强FLX代谢产物理化性质和生态毒性的研究，并考察水质因素(pH、溶解性有机质、离子强度、温度等)及水动力变化对FLX及代谢产物生物累积和生物效应的影响，从而建立水质和水动力学模型综合分析不同水环境FLX污染的生态风险。

c. 结合水生态系统的食物链结构，研究水环境中FLX在食物链不同营养级生物间的传递和代谢转化过程。建立从种群、个体、器官组织、细胞到基因的不同水平的毒理学指标体系，全面掌握FLX对生态系统及人体健康的潜在危害，最终建立起FLX污染的生态风险评价体系。

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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

国家自然科学基金(51509071)；江苏省自然科学基金(BK20150801)

闫振华(1987—)，男，讲师，博士，主要从事水体复合污染等研究。E-mail:hwahuer@hhu.edu.cn

陆光华，教授。E-mail:ghlu@hhu.edu.cn

X522

A

1004-6933(2017)06-0147-08

2017-04-17 编辑：王 芳)