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非甾体抗炎药(non-steroidal anti-inflammatory drugs, NSAIDs)是一类不具有甾体结构的抗炎药,有消炎、镇痛、退热等功效,每年全球的处方量可达5亿[1]. 布洛芬(ibuprofen, IBP)作为一种典型的NSAIDs,在临床应用中安全有效. 它不仅在退热效果、时间和镇痛等方面都具有显著优势,并且副作用小,易于耐受. 在解热镇痛方面,IBP与对乙酰氨基酚和阿司匹林并称三大支柱药物[2]. 自20世纪70年代末,IBP开始在我国生产销售. 据统计,1999年到2018年的近三十年间,全国IBP原料药产量从由581 t增长到
9200 t,增长超过14倍,已成为人们生活中的必备药品[3]. 2020年以来,新冠肺炎的肆虐导致了全球范围内的用药需求增加. 其中,IBP等NSAIDs因其可以缓解感染者的发烧、肌肉酸痛等不适症状而被广泛使用,国务院联防联控机制发布的新冠感染者居家治疗指南及常用药参考中,IBP也作为针对发热症状的药物被列入其中.虽然IBP在预防和治疗人类和动物疾病方面具有重要作用,但其生产、使用和处理过程中也会大量释放进入环境,对周围生态环境造成巨大的压力. 现有数据表明,IBP在环境介质中广泛存在. 德国、西班牙河流地表水IBP含量分别最高可达2.38、11.89 μg·L−1;污水处理厂进水中IBP含量高于河流,加拿大污水处理厂进水中IBP的最高含量可达到75.8 μg·L−1[4]. 在对各大洲的71个国家环境检测中发现亚太和非洲地区的地表水中的IBP含量最高分别达20.5 μg·L−1和21.0 μg·L−1,全球IBP浓度最高的地区是西欧,其最高检测浓度为303 μg·L−1[5]. 由于海洋作为许多地表河流的汇流地和沿海排污的受纳水体,因此在世界各地的海水中也普遍检测到了IBP的存在. 环境调查与监测发现,位于法国南岸的地中海区域海水中发现了浓度约
1500 ng·L−1的IBP[6]. 在对巴西沿海地区药物的一项研究表明,海水样品中IBP存在普遍性,其浓度范围为326.1—2094.4 ng·L−1[7].目前关于IBP对水生生物毒性效应研究相对较少,且主要是针对淡水物种[8]. 斑马鱼暴露于50、500 μg·L−1浓度下的IBP后,其胚胎的孵化时间明显延迟,胚胎内自发运动显著减少,仔鱼的运动能力减弱[9]. IBP浓度为1.5 μg·L−1时,鲤鱼胚胎的死亡率和畸形率开始大幅增加,并且这些增加呈浓度和时间依赖性[4]. 将蓝贻贝暴露于不同浓度的IBP中,发现贻贝的生长空间缩小,足丝强度、数量均有所下降,表明IBP的存在无论浓度高低,均不利于贻贝的生长和生存[10]. 因此,亟需开展IBP对海洋生物毒性效应的研究,以探究其毒性作用的程度,评估其对海洋生物的潜在危害,并为海洋生态风险评估提供参考依据.
鱼类属低等脊椎动物,在水生态系统食物链中占据重要的位置,是水生生物不可或缺的代表,且与人类的关系密切,作为生态毒理研究材料具有较好的代表性[11]. 海洋青鳉鱼(Oryzias melastigma, O.M.)作为国际生命科学学会(ILSI)与健康和环境科学研究所(HESI)推荐的毒理学研究模型,具有青鳉属物种共有的优势[12],如易于大规模饲养、性别易辨别、世代周期短、对污染物敏感、易于观察等[13]. 本实验选用O.M.作为受试物种,研究了不同浓度IBP暴露对O.M.早期生命阶段的发育毒性、抗氧化系统和神经递质系统影响,为评估IBP潜在的生态风险提供了参考依据.
布洛芬对海洋青鳉鱼生命初期毒性效应
Toxic effects of ibuprofen on early life stages of marine medaka (Oryzias Melastigma)
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摘要: 为探究布洛芬(Ibuprofen,IBP)对海洋青鳉鱼(Oryzias melastigma)早期生命阶段的毒性效应,将海洋青鳉鱼胚胎在不同浓度(0、1、10、100、
1000 μg·L−1)IBP溶液中暴露至孵化后的第30 天(未孵化胚胎暴露20 d). 观察统计胚胎的孵化率、孵化时间、心率、仔鱼30 d存活率以及体长体重等发育参数,并检测胚胎的抗氧化酶(超氧化物歧化酶(superoxide dismutase,SOD)、过氧化氢酶(catalase,CAT)、谷胱甘肽巯基转移酶(Glutathione S-transferase,GST))活性、抗氧化剂(还原型谷胱甘肽(glutathione,GSH))、氧化产物(丙二醛(malonic dialdehyde,MDA))浓度和神经递质降解酶(乙酰胆碱酯酶(acetylcholinesterase,AChE))活性变化,以评估IBP对海洋青鳉鱼早期生命阶段的发育毒性、抗氧化系统以及神经递质系统的影响. 结果表明,1 μg·L−1IBP对海洋青鳉鱼胚胎及仔鱼不存在发育毒性,其余各浓度导致胚胎孵化率、孵化时间、心率和仔鱼存活率降低,所有浓度下仔鱼体长体重均未变化;在第5天时,随浓度升高,SOD活性和GSH含量呈下降趋势,CAT、GST活性和MDA含量先上升后下降,第8天时各指标趋于正常;IBP浓度的升高导致AChE活性先增加后降低. 综上,环境相关浓度下的IBP对海洋青鳉鱼胚胎及仔鱼不存在发育毒性,各浓度IBP均会导致胚胎产生氧化应激和神经毒性效应.Abstract: To investigate the toxic effects of ibuprofen (IBP) on the early life stages of marine medaka (Oryzias melastigma), marine medaka embryos were exposed to different concentrations (0, 1, 10, 100, and1000 μg·L−1) of IBP solution until 30 days after hatching (20 days for unhatched embryos). Various developmental parameters, including hatching rate, hatching time, heart rate, 30-day survival rate of larvae, body length and weight, were observed and recorded. Additionally, measurements were conducted to assess the activity of antioxidant enzymes (superoxide dismutase, SOD; catalase, CAT; glutathione S-transferase, GST), levels of antioxidant (glutathione, GSH), concentrations of oxidative product (malonic dialdehyde, MDA), and the activity of neurotransmitter degrading enzyme (acetylcholinesterase, AChE) in the embryos. These measurements aimed to evaluate the developmental toxicity, antioxidant system, and neurotransmitter system effects of Ibuprofen on the early life stages of marine medaka. The results indicated that IBP at a concentration of 1 μg·L−1 did not induce developmental toxicity in marine medaka embryos and larvae. However, exposure to higher concentrations resulted in decreased hatching rate, hatching time, heart rate, and larval survival rate, while no significant changes in body length and weight were observed across all concentrations. On the 5th day, increasing IBP concentration led to a decreasing trend in SOD activity and GSH content, while CAT and GST activities, as well as MDA levels, initially increased and then decreased, with all indicators returning to normal levels by the 8th day. Moreover, the increase in IBP concentration led to an initial increase and subsequent decrease in AChE activity. In conclusion, environmentally relevant concentrations of IBP did not exhibit developmental toxicity in marine medaka embryos and larvae. However, all tested concentrations of IBP resulted in oxidative stress and neurotoxic effects in the embryos. -
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