氟喹诺酮类抗生素环境行为及其生态毒理研究进展

孟磊，杨兵，薛南冬

中国环境科学研究院 环境基准与风险评估国家重点实验室，北京100012

氟喹诺酮类抗生素环境行为及其生态毒理研究进展

孟磊，杨兵，薛南冬*

中国环境科学研究院 环境基准与风险评估国家重点实验室，北京100012

氟喹诺酮类抗生素(FQs)是治疗人和动物细菌性感染的高效广谱抗菌药，随着氟喹诺酮类抗生素在禽畜养殖业的广泛使用，由此引起的环境污染受到人们的关注。本文综述了氟喹诺酮类抗生素在水体、土壤/沉积物中的污染现状、吸附降解环境行为及其生态毒理研究进展。FQs抗生素的环境行为和风险应从环境多介质层面进行评估，同时应加强对生态毒性机理以及与其他环境污染物的联合毒性效应的研究。

氟喹诺酮；抗生素；污染现状；环境行为；吸附和降解；生态毒理

氟喹诺酮类(fluoroquinolones, FQs)抗生素是一类由人工合成的广谱类抗菌药，是喹诺酮的哌嗪基派生物，它通过抑制细菌的DNA解旋酶II(topoisomerase II)和拓扑异构酶IV(topoisomerase IV)而影响细菌的DNA复制过程[1]。FQs药物都具有酮酸的共同骨架结构(图1)，FQs抗生素是在喹诺酮类抗生素的基础上，在第一代萘啶酸和第二代吡哌酸的引入氟原子开发出的。常用的FQs药物主要有诺氟沙星(norfloxacin)、恩诺沙星(enrofloxacin)、环丙沙星(ciprofloxacin)、洛美沙星(lomefloxacin)、氧氟沙星(ofloxacin)、沙拉沙星(sarafloxacin)、培氟沙星(pefloxacin)、依诺沙星(enoxacin)、氟罗沙星(fleroxacin)和二氟沙星(difloxacin)等[2]。由于FQs抗生素在治疗人和动物细菌性感染具有良好的药物动力学特性及治疗效果，应用广、使用量大。据统计，喹诺酮药物的使用量已位于抗感染药物前列，2009年，占据全球抗生素17%的市场份额[3]。WHO(1998年)调查显示[4]，据美国、日本、韩国和欧盟等国家和组织的统计，年消费喹诺酮类药物中作为专用产品约有50 t，作为通用产品70 t，在中国分别为l 350 t和470 t。其中，诺氟沙星、环丙沙星和氧氟沙星的生产量最大[5]。而抗生素进入人或动物体内后40%～90%以母体或代谢物的形式随畜禽粪便进入环境[6]。2010年，在中国排放到环境中畜禽粪便的量达45亿t。环境调查发现，FQs抗生素在水体、沉积物、土壤等多种环境介质中都有检出[7-8]。在一些养殖场周围的水体和土壤中，抗生素含量可达到异常高的水平[9-10]。目前，尽管国内外定期推出抗生素用药使用原则，但尚无FQs抗生素的环境标准。研究表明，环境中抗生素可能导致生物毒性和致病菌产生抗药性基因等环境风险和生态风险[11]，因此，抗生素引起的环境污染引起人们的高度关注和重视，对FQs抗生素的环境污染现状、环境行为和生态毒性日益成为环境科学的研究热点。本文介绍了FQs抗生素在环境多介质中的污染现状，综述了它们的环境行为和生态毒理研究进展。

图1 氟喹诺酮类抗生素的分子结构Fig. 1 The molecular structure of the fluoroquinolone antibiotics

1 FQs抗生素污染(FQs antibiotics pollution)

1.1 水体FQs抗生素污染

不同水环境(污水处理厂、医院废水、养殖废水、地表水、地下水、饮用水)中FQs抗生素种类及污染水平见表1。由表1可知，水环境中FQs抗生素以诺氟沙星、环丙沙星、氧氟沙星污染较为普遍，其浓度也较高。FQs抗生素在污废水中的残留量与污水的来源和特性有关，污水处理厂、医院污水、养殖废水中抗生素含量较高，浓度在μg·L-1级。如在美国在医院废水中检出氧氟沙星的浓度达25.5～35.5 μg·L-1[12]。各地不同污水处理厂中FQs抗生素浓度差异很大，浓度范围在0.013～13.625 μg·L-1之间。与污水相比，地表水和地下水中抗生素含量相对较低(浓度在ng·L-1级)。一般污水处理厂的抗生素去除效率在60%到90%，因此，尽管城市污水大部分进入污水处理系统，也可能存在抗生素对地表水、饮用水源和地下水污染[13]。

1.2 土壤/沉积物中FQs抗生素的污染

表2列出了不同地区土壤/沉积物中FQs抗生素的污染水平。由表2可以看出，不同国家和地区土壤/沉积物中FQs抗生素的种类和污染水平存在差异，这与抗生素的用量、畜禽粪肥的施用量、环境条件等差异相关[39]。土壤/沉积物中FQs抗生素以诺氟沙星、环丙沙星、恩诺沙星、氧氟沙星污染为主，含量在μg·kg-1～mg·kg-1数量级范围。如在西班牙Morales-Muoz等[40]检测到土壤中高浓度FQs抗生素，在施用粪肥的2处土壤中诺氟沙星浓度分别为6.2 mg·kg-1和9.8 mg·kg-1，环丙沙星的浓度分别为3 mg·kg-1和5.8 mg·kg-1。在瑞士Golet等[41]检测到土壤中环丙沙星的浓度为1.96 mg·kg-1。中国山东省中北部和珠江三角洲菜地土壤中检出诺氟沙星的最高浓度分别为288.3 μg·kg-1和150.2 μg·kg-1，环丙沙星的最高检出浓度分别为651.6 μg·kg-1和119.8 μg·kg-1[42-43]。与其他环境介质相比，污泥中FQs抗生素的污染更重，中国污泥中氧氟沙星残留浓度高达21 mg·kg-1[44]，其他国家FQs在污泥中检出浓度在0.04～8.3 mg·kg-1范围内。在畜禽粪便中，Zhao等[45]检测到我国猪粪中恩诺沙星浓度为33.26 mg·kg-1，环丙沙星浓度为33.98 mg·kg-1。可见，我国土壤/沉积物中FQs抗生素污染相对较严重。

表1 水体中氟喹诺酮类抗生素的污染水平Table 1 The concentrations of fluoroquinolone antibiotics in water

表2 土壤/沉积物中氟喹诺酮类抗生素的污染水平Table 2 The concentrations of fluoroquinolone antibiotics in soils and sediments

2 FQs抗生素的环境行为(Environmental behaviorsof FQs antibiotics)

FQs抗生素按用途分为人用和兽用两类。环境中FQs抗生素主要来源于工业排放、医院排放、废物垃圾、畜禽排泄、水产养殖等，进入环境中的抗生素经过吸附、迁移、转化、降解(光解、水解和生物降解)等过程在土壤、水和沉积物等环境介质间再分配。图2 环境中FQs抗生素的来源和迁移途径示意图。

图2 环境中氟喹诺酮类抗生素的来源和迁移Fig. 2 Sources and pathways of fluoroquinolone antibiotics in environment

2.1 环境中FQs的吸附

抗生素进入土壤途径主要包括施用含有抗生素的粪肥、污泥和含抗生素的污水灌溉[58-59]。进入土壤中的抗生素可通过吸附作用停留在土壤中，而影响其吸附的主要因素有土壤矿物质、有机质、多价态金属阳离子及污泥等。FQs抗生素容易在土壤表层积累，向下层土的迁移很弱，这与-COOH对FQs抗生素吸附的贡献较大有关[60-63]；喹诺酮类抗生素吸附系数(Kd)值较大，吸附能力较强，易在土壤中蓄积[64]。土壤对恩诺沙星具有较强的吸附作用，其中青紫泥田和黄泥砂田的Kd值较高, 分别在3 694～5 546 L·kg-1和3 800～4 696 L·kg-1之间，残留在土壤中的低量恩诺沙星主要被吸附在固体颗粒上，不易释放和随水迁移[65]。一些多价态金属阳离子是影响部分抗生素吸附行为的重要因素。FQs抗生素能和金属离子(Ca2+、Mg2+、Fe3+或Al3+)形成络合物，使其在环境介质中较稳定存在[66]。水体和污水处理中的FQs抗生素也可以通过污泥吸附的方式去除。FQs从废水中转移到活性污泥中，从而达到去除目的[67]，环丙沙星通过污泥吸附去除率也达到60%[68]。

2.2 环境中FQs的降解

降解是环境抗生素重要的代谢途径，包括光解、水解和生物降解。FQs抗生素在环境介质中主要发生光解和生物降解等降解过程，很难发生水解作用[69-70]。

FQs抗生素属光降解敏感型，主要降解产物包括10多种有机物及F-和HCOO-等离子。FQs的光解路径依赖于母体结构，对于哌嗪环N4-烷基取代的FQs，N4-烷基脱除为最主要的光解路径，而对于N4-H结构的FQs，光导致脱羧和羟基化脱氟为重要的光解反应路径[71-72]。FQs通过母体萘啶环上取代基的脱除而生成中间产物，易进入发光菌的细胞而产生毒性[73-74]。Yuan等[75]研究发现环丙沙星在一定紫外光强下的降解产物对费氏弧菌的毒性比母体化合物更强。表3列出了不同环境介质中FQs抗生素光解的半衰期。由表3可以看出，光解是地表水中的FQs抗生素主要降解方式[76-77]，但降解过程缓慢，导致在环境中的残留时间比较久。沉积物中FQs的光解只发生在沉积物表层[78]，且相当缓慢。而土壤中吸附的FQs抗生素充分暴露于自然光下，能很好地促使它们降解[79]。Sturini等[80]研究了土壤中2种FQs抗生素恩诺沙星和麻保沙星的光解作用，实验结果表明，经过50 h后2种FQs的降解率达到80%。

表3 环境中氟喹诺酮类抗生素光解的半衰期Table 3 Half-life of fluoroquinolone antibiotics photolysis in environment

生物降解是抗生素在环境中降解的重要的途径。被生物降解的抗生素，可能转化为生物体的组成部分或是最终转化为无机或有机小分子。FQs的生物降解主要是母体结构脱-H2O、-HF、-CO2等，打断哌嗪取代基，产生一系列的降解产物。Ailette Prieto等[84]研究了白腐真菌对环丙沙星和诺氟沙星的降解过程，环丙沙星的降解产物为Cip-1(C15H17FN3O3), Cip-2(C13H12FN2O3), Cip-3(C17H19FN3O4), Cip-4(C17H17FN3O5)等。Alexy等[85]在密闭瓶中模拟18种抗生素的降解实验表明，氧氟沙星的生物降解率较低仅为7.5%，而其它类抗生素如苄青霉素和金霉素则被完全降解。Boxall等[86]报道了喹诺酮类抗生素在粪便中的半衰期为100 d。

废水处理中FQs的生物降解研究发现，FQs的生物降解<10%，几乎可以忽略[87]；而在活性污泥反应器中进行生物降解试验，结果表明添加250 μg·kg-1的环丙沙星，2.5 d之后，去除率达50%[88]；在硝化条件下，FQs生物降解的去除率达60%[89]；Li和Zhang等[90]研究了污泥中环丙沙星、氧氟沙星、恩诺沙星的生物降解，48 h之后，去除率达40%。目前，研究者多认为，FQs的主要去除机制是活性污泥的吸附，而非生物降解[91-92，87]。

3 FQs抗生素的生态毒理(Ecological toxicologyof FQs antibiotics)

相对较低浓度的恩诺沙星残留对土壤微生物群落多样性的影响不明显，而相对较高浓度的恩诺沙星残留则降低了其微生物群落的多样性，即药物浓度越高，则土壤微生物多样性就越低[93]。马驿等[94]发现恩诺沙星药物浓度大于或等于0.1 μg·kg-1可显著降低土壤微生物的丰富度和多样性，药物浓度越高，土壤微生物的丰富度和多样性就越低。显然，FQs进入土壤环境中会导致土壤微生物多样性的下降。

土壤呼吸作用反映了土壤微生物的总活性，可以用来作为监测土壤生态环境变化的重要指标[95]。诺氟沙星在浓度为小于1 mg·kg-1时，对土壤微生物呼吸都有一定的抑制作用，浓度大于5 mg·kg-1为激活作用，激活作用随着处理浓度的增加而升高，恩诺沙星对呼吸的影响随浓度变化变化先激活后抑制[96]。恩诺沙星残留在土壤中作用达2～4 d 时，较低浓度的恩诺沙星对土壤呼吸作用有刺激作用，较高浓度则对其产生抑制作用[97]。王丽平等[98]也发现，低质量分数的恩诺沙星(0.1 mg·kg-1)可刺激土壤中微生物的生长和呼吸作用，而高质量分数的恩诺沙星(2～20 mg·kg-1)会抑制土壤微生物活性和有机碳的矿化。恩诺沙星还影响土壤微生物功能，进而对土壤特性和土壤呼吸作用、纤维分解作用、以及氨化作用等生态过程造成影响。研究还发现，恩诺沙星可显著抑制土壤脱氢酶和磷酸酶的活性，抑制土壤微生物的呼吸强度和硝化作用，土壤微生物群落功能多样性(基于Biolog方法)随恩诺沙星浓度升高显著降低[99]。可以推测抗生素对土壤微生物呼吸的激活作用，可能因为抗生素被某些微生物利用作为自身生长的碳源，促进微生物的生长，对微生物呼吸起到促进作用[100-101]。要明确抗生素对土壤微生物的影响机理，需要通过生理生化测定方法和分子生物学手段来分析测定更多的指标来综合评价。

环境中抗生素残留对植物的生态毒性效应的研究目前报道的还较少且主要集中在实验室模拟条件下水生植物和陆生植物的毒性研究。Migliore等[102]研究表明低浓度恩诺沙星(50～100 μg·L-1)促进了香瓜、莴苣、萝卜和菜豆的生长，高浓度则显著抑制了这4种作物主根、胚轴、子叶的长度，降低了叶片数量，其中对根的抑制效果最明显，这可能与FQs抗生素在植物根部的蓄积量有关，在根部蓄积量最多，因此表现出对根生长的抑制作用最为显著。Boxall等[103]研究发现，土培条件下1 mg·kg-1恩诺沙星显著抑制胡萝卜和莴苣生长，而相同浓度的阿莫西林、磺胺嘧啶、泰乐素、甲氧苄啶和氟苯尼考等其生长影响不显著。金彩霞等[104]采用室内生长箱培养方法，研究了环丙沙星对小麦、白菜和番茄种子发芽、根伸长、芽伸长的影响，结果表明，作物根伸长和芽伸长的抑制率随着土壤中环丙沙星含量的增高而增大，两者呈正相关(P< 0.05)。与根伸长和芽伸长抑制相比, 植物种子发芽对抗生素胁迫的敏感性较弱。

FQs抗生素对水生生物药害作用较强[105]。不同抗生素对水生生物的半最大效应浓度(EC50，μg·L-1)影响有差异。表4列出了FQs抗生素对不同水生生物体的EC50，由表可知EC50介于μg·L-1～ mg·L-1之间。蓝藻在水生生物体中最为敏锐，藻类和植物比无脊椎动物和鱼较敏锐。FQs浓度较高时，会对生物体产生急性毒性，但是长期暴露在低浓度下产生的副作用也不容被忽视[106-107]。Martins等[108]实验表明，长期暴露在低浓度的环丙沙星下会对Daphnia magna产生慢性损害。

FQs抗生素诱发水生动物的毒性，鱼类对FQs抗生素的代谢过程中会产生一些具有亲电子活性的中间产物，可能诱导生物体内抗氧化酶活性的变化，进而造成机体的氧化应激效应[109]，导致机体代谢紊乱，引发其他疾病。有研究发现恩诺沙星会引起鱼脑和肝脏内谷胱甘肽含量降低，过氧化氢酶和谷胱甘肽转移酶活性发生变化，诱导鱼体内脂质过氧化和神经功能障碍等疾病[109]，并证实在鲈鱼体内恩诺沙星主要是通过细胞色素代谢为环丙沙星，且恩诺沙星对细胞色素具有明显的抑制作用[110]。

表4 氟喹诺酮类抗生素对水生物种的半最大效应浓度(EC50)Table 4 The concentration for 50% of maximal effect of fluoroquinolone antibiotics on aquatic species

抗生素种类繁多，降解和代谢产物复杂，近年来，研究者对抗生素的联合毒性作用主要集中在四环素和磺胺类抗生素[119-121]，对FQs抗生素研究甚少，环境中共存的FQs抗生素及其转化产物之间的联合毒性作用还有待进一步研究。

4 结论(Conclusion)

FQs抗生素作为环境中一类新型污染物，在环境中普遍存在，对人类健康和生态环境构成威胁。FQs抗生素水体含量在ng·L-1～μg·L-1之间，土壤/沉积物含量在μg·kg-1～mg·kg-1数量级，其中诺氟沙星、环丙沙星、恩诺沙星、氧氟沙星浓度相对较高。环境行为和生态毒理研究表明，FQs抗生素在环境介质中吸附能力较强，在环境中主要通过光解和生物降解等途径降解；FQs抗生素污染导致土壤微生物的多样性下降和微生物活性降低，抑制植物的生长发育，对水生生物产生生态毒性效应。FQs抗生素的环境风险应从环境多介质层面进行评估，同时应加强对生态毒性机理以及与其他环境污染物的联合毒性效应研究。

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A Review on Environmental Behaviors and Ecotoxicology of Fluoroquinolone Antibiotics

Meng Lei, Yang Bing, Xue Nandong*

State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China

18 November 2014 accepted 7 January 2015

Fluoroquinolone antibiotics (FQs) were the broad-spectrum antibacterial drugs which were widely applied in livestock and poultry breeding industry to treat bacterial infection. The pollution of FQs in environment has been widely concerned. Environmental behaviors such as adsorption and desorption in water and soil/sediment and ecotoxicology of FQs were summarized in the paper. It is suggested that environmental behaviors and risk of FQs should be assessed at the level of environmental multimedia. More study should be conducted on ecological toxicity mechanism of FQs as well as on effects of the joint toxicity with other environmental pollutants.

fluoroquinolone; antibiotics; pollution situation; environmental behaviors; adsorption and desorption; ecotoxicology

国家高技术研究发展计划(863)项目(2012AA06A304)

孟磊(1987-)，女，硕士，研究方向为土壤中有机污染物环境化学行为，E-mail: zimin616@163.com；

*通讯作者(Corresponding author)， E-mail: xuend@craes.org.cn

10.7524/AJE.1673-5897.20141118006

2014-11-18 录用日期：2015-01-07

1673-5897(2015)2-76-13

X171.5

A

薛南冬(1964-)，男，理学博士，研究员，主要研究方向为土壤有机物污染及其环境修复，土壤化学品污染与控制等，发表学术论文90余篇。

孟磊, 杨兵, 薛南冬. 氟喹诺酮类抗生素环境行为及其生态毒理研究进展[J]. 生态毒理学报, 2015, 10(2): 76-88

Meng L, Yang B, Xue N D. A review on environmental behaviors and ecotoxicology of fluoroquinolone antibiotics [J]. Asian Journal of Ecotoxicology, 2015, 10(2): 76-88 (in Chinese)