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麻醉剂依托咪酯诱导斑马鱼幼鱼神经发育毒性

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马栋栋, 李思颖, 张金阁, 卢志杰, 龙小冰, 黄争, 黄楚舒, 刘昕, 史文俊, 应光国. 麻醉剂依托咪酯诱导斑马鱼幼鱼神经发育毒性[J]. 生态毒理学报, 2024, 19(1): 40-53. doi: 10.7524/AJE.1673-5897.20230928002
引用本文: 马栋栋, 李思颖, 张金阁, 卢志杰, 龙小冰, 黄争, 黄楚舒, 刘昕, 史文俊, 应光国. 麻醉剂依托咪酯诱导斑马鱼幼鱼神经发育毒性[J]. 生态毒理学报, 2024, 19(1): 40-53. doi: 10.7524/AJE.1673-5897.20230928002
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Ma Dongdong, Li Siying, Zhang Jinge, Lu Zhijie, Long Xiaobing, Huang Zheng, Huang Chushu, Liu Xin, Shi Wenjun, Ying Guangguo. Developmental Neurotoxicity of Anesthetic Etomidate on Zebrafish Larvae[J]. Asian journal of ecotoxicology, 2024, 19(1): 40-53. doi: 10.7524/AJE.1673-5897.20230928002
Citation: Ma Dongdong, Li Siying, Zhang Jinge, Lu Zhijie, Long Xiaobing, Huang Zheng, Huang Chushu, Liu Xin, Shi Wenjun, Ying Guangguo. Developmental Neurotoxicity of Anesthetic Etomidate on Zebrafish Larvae[J]. Asian journal of ecotoxicology, 2024, 19(1): 40-53. doi: 10.7524/AJE.1673-5897.20230928002
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麻醉剂依托咪酯诱导斑马鱼幼鱼神经发育毒性

  • 1. 华南师范大学环境研究院广东省化学污染与环境安全重点实验室, 华南师范大学环境理论化学教育部重点实验室, 广州 510006;

  • 2. 华南师范大学环境学院, 广州 510006;

  • 3. 广东省毒品实验技术中心(国家毒品实验室广东分中心), 广东省精神活性物质监测与安全重点实验室, 广州 510230

    • 作者简介: 马栋栋(1991-),男,博士研究生,研究方向为生态毒理学,E-mail:dongdong.ma@m.scnu.edu.cn
    通讯作者: 刘昕,E-mail: 87541944@qq.com;  史文俊,E-mail: wenjun.shi@m.scnu.edu.cn; 
  • 基金项目:

    国家自然科学基金资助项目(42277268)；广东省精神活性物质监测与安全重点实验室研究基金项目(2020B22101007)

  • 中图分类号: X171.5

Developmental Neurotoxicity of Anesthetic Etomidate on Zebrafish Larvae

  • 1. SCNU Environmental Research Institute, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety & MOE Key Laboratory of Environmental Theoretical Chemistry, South China Normal University, Guangzhou 510006, China;

  • 2. School of Environment, South China Normal University, Guangzhou 510006, China;

  • 3. Anti-Drug Technology Center of Guangdong Province (National Anti-Drug Laboratory Guangdong Regional Center), Guangdong Provincial Key Laboratory of Psychoactive Substances Monitoring and Safety, Guangzhou 510230, China

    • Corresponding authors: Liu Xin ;  Shi Wenjun ; 
  • Fund Project:

  • 摘要: 依托咪酯(etomidate, ET)在临床上常被用作麻醉剂。ET长期高剂量地使用会导致人类意识下降和认知障碍等负面效应。但ET对鱼类的神经毒性机制尚不清楚。在本文中，2 hpf (hours post-fertilization)的斑马鱼胚胎暴露于不同浓度ET (0.010、0.091、0.501、9.400、84.31和664.4 μg·L-1)至168 hpf。通过分析ET对斑马鱼胚胎生理发育、早期行为、细胞凋亡以及多巴胺(dopamine, DA)和γ氨基丁酸(gamma aminobutyric acid, GABA)通路相关基因转录表达水平的影响，评估其对斑马鱼幼鱼神经发育毒性。结果表明，664.4 μg·L-1 ET显著增大48 hpf和60 hpf斑马鱼胚胎孵化率。0.091 μg·L-1和0.501 μg·L-1 ET诱导168 hpf幼鱼体长减少。0.010、0.091、0.501、9.400、84.31和664.4 μg·L-1 ET增大48 hpf胚胎畸形评分。0.501、9.400、84.31和664.4 μg·L-1 ET暴露显著增大96 hpf胚胎畸形评分。0.501、9.400和664.4 μg·L-1 ET显著增大168 hpf胚胎畸形评分。0.010 μg·L-1 ET促进了大脑细胞凋亡，而664.4 μg·L-1 ET抑制了大脑细胞凋亡。行为分析显示，ET所有浓度均抑制触碰行为。0.091 μg·L-1 ET增强幼鱼游泳行为，而664.4 μg·L-1 ET减弱游泳行为。并且ET以浓度依赖的方式导致焦虑行为增加。qPCR分析结果表明，低浓度ET显著上调了DA和GABA通路相关基因的转录表达水平，而高浓度ET显著抑制了这些基因的转录表达水平。这些结果表明，ET对发育早期斑马鱼具有明显的神经发育毒性。
    Abstract: Etomidate (ET) is widely used as an anesthetic in clinical practice. The long-term use of ET can lead to negative effects, such as decreased consciousness and cognitive impairment. However, the developmental neurotoxicity of ET on fish remains unclear. To address this issue, zebrafish embryos were exposed to ET from 2 hpf (hours post-fertilization) to 168 hpf at 0.010, 0.091, 0.501, 9.400, 84.31 and 664.4 μg·L-1. The physiological development, behavior and cell apoptosis, and transcriptional expression of genes related to dopamine (DA) and γ-aminobutyric acid (GABA) pathway were detected to investigate the developmental neurotoxicity of ET. The results showed that 664.4 μg·L-1 ET decreased hatching rate at 48 hpf and 60 hpf. 0.091 μg·L-1 and 0.501 μg·L-1 ET decreased body length in larvae at 168 hpf. At 48 hpf, 0.010, 0.091, 0.501, 9.400, 84.31 and 664.4 μg·L-1 ET increased malformation. 0.501, 9.400, 84.31 and 664.4 μg·L-1 ET increased malformation at 96 hpf. Additionally, 0.501, 9.400 and 664.4 μg·L-1 ET increased malformation at 168 hpf. The 0.010 μg·L-1 ET caused cell apoptosis in the brain, while 664.4 μg·L-1 ET inhibited apoptosis. In addition, behavior analysis indicated that ET inhibited touch behavior at all concentrations. The 0.091 μg·L-1 ET enhanced swimming behavior in zebrafish larvae, while 664.4 μg·L-1 ET weakened swimming behavior. ET increased anxious behavior in a concentration-dependent manner. The qPCR data showed that ET up-regulated the transcriptions of genes related to DA and GABA pathway at low concentration, while ET down-regulated the transcriptions of these genes at high concentration. The above results indicate that ET has significant neurodevelopmental toxicity in early development of zebrafish.
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  • 收稿日期:  2023-09-28
马栋栋, 李思颖, 张金阁, 卢志杰, 龙小冰, 黄争, 黄楚舒, 刘昕, 史文俊, 应光国. 麻醉剂依托咪酯诱导斑马鱼幼鱼神经发育毒性[J]. 生态毒理学报, 2024, 19(1): 40-53. doi: 10.7524/AJE.1673-5897.20230928002
引用本文: 马栋栋, 李思颖, 张金阁, 卢志杰, 龙小冰, 黄争, 黄楚舒, 刘昕, 史文俊, 应光国. 麻醉剂依托咪酯诱导斑马鱼幼鱼神经发育毒性[J]. 生态毒理学报, 2024, 19(1): 40-53. doi: 10.7524/AJE.1673-5897.20230928002
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Ma Dongdong, Li Siying, Zhang Jinge, Lu Zhijie, Long Xiaobing, Huang Zheng, Huang Chushu, Liu Xin, Shi Wenjun, Ying Guangguo. Developmental Neurotoxicity of Anesthetic Etomidate on Zebrafish Larvae[J]. Asian journal of ecotoxicology, 2024, 19(1): 40-53. doi: 10.7524/AJE.1673-5897.20230928002
Citation: Ma Dongdong, Li Siying, Zhang Jinge, Lu Zhijie, Long Xiaobing, Huang Zheng, Huang Chushu, Liu Xin, Shi Wenjun, Ying Guangguo. Developmental Neurotoxicity of Anesthetic Etomidate on Zebrafish Larvae[J]. Asian journal of ecotoxicology, 2024, 19(1): 40-53. doi: 10.7524/AJE.1673-5897.20230928002
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麻醉剂依托咪酯诱导斑马鱼幼鱼神经发育毒性

    通讯作者: 刘昕,E-mail: 87541944@qq.com;  史文俊,E-mail: wenjun.shi@m.scnu.edu.cn; 
    作者简介: 马栋栋(1991-),男,博士研究生,研究方向为生态毒理学,E-mail:dongdong.ma@m.scnu.edu.cn
  • 1. 华南师范大学环境研究院广东省化学污染与环境安全重点实验室, 华南师范大学环境理论化学教育部重点实验室, 广州 510006;
  • 2. 华南师范大学环境学院, 广州 510006;
  • 3. 广东省毒品实验技术中心(国家毒品实验室广东分中心), 广东省精神活性物质监测与安全重点实验室, 广州 510230
  • 收稿日期:  2023-09-28
基金项目:

国家自然科学基金资助项目(42277268)；广东省精神活性物质监测与安全重点实验室研究基金项目(2020B22101007)

摘要: 依托咪酯(etomidate, ET)在临床上常被用作麻醉剂。ET长期高剂量地使用会导致人类意识下降和认知障碍等负面效应。但ET对鱼类的神经毒性机制尚不清楚。在本文中，2 hpf (hours post-fertilization)的斑马鱼胚胎暴露于不同浓度ET (0.010、0.091、0.501、9.400、84.31和664.4 μg·L-1)至168 hpf。通过分析ET对斑马鱼胚胎生理发育、早期行为、细胞凋亡以及多巴胺(dopamine, DA)和γ氨基丁酸(gamma aminobutyric acid, GABA)通路相关基因转录表达水平的影响，评估其对斑马鱼幼鱼神经发育毒性。结果表明，664.4 μg·L-1 ET显著增大48 hpf和60 hpf斑马鱼胚胎孵化率。0.091 μg·L-1和0.501 μg·L-1 ET诱导168 hpf幼鱼体长减少。0.010、0.091、0.501、9.400、84.31和664.4 μg·L-1 ET增大48 hpf胚胎畸形评分。0.501、9.400、84.31和664.4 μg·L-1 ET暴露显著增大96 hpf胚胎畸形评分。0.501、9.400和664.4 μg·L-1 ET显著增大168 hpf胚胎畸形评分。0.010 μg·L-1 ET促进了大脑细胞凋亡，而664.4 μg·L-1 ET抑制了大脑细胞凋亡。行为分析显示，ET所有浓度均抑制触碰行为。0.091 μg·L-1 ET增强幼鱼游泳行为，而664.4 μg·L-1 ET减弱游泳行为。并且ET以浓度依赖的方式导致焦虑行为增加。qPCR分析结果表明，低浓度ET显著上调了DA和GABA通路相关基因的转录表达水平，而高浓度ET显著抑制了这些基因的转录表达水平。这些结果表明，ET对发育早期斑马鱼具有明显的神经发育毒性。

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