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研究生: 林佳柔
Lin, Jia-Rou
論文名稱: 粘桿菌素對斑馬魚胚胎之毒性並探討鈣離子對粘桿菌素的影響
Investigation of the toxicity of colistin in zebrafish embryos and the influence of calcium on the toxicity
指導教授: 林豊益
Lin, Li-Yih
口試委員: 林豊益
Lin, Li-Yih
洪君琳
Horng, Jiun-Lin
周銘翊
Chou, Ming-Yi
口試日期: 2021/07/27
學位類別: 碩士
Master
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2021
畢業學年度: 109
語文別: 中文
論文頁數: 71
中文關鍵詞: 粘桿菌素毒性毛細胞角質細胞離子細胞
英文關鍵詞: colistin, toxicity, hair cell, keratinocyte, ionocyte
研究方法: 實驗設計法
DOI URL: http://doi.org/10.6345/NTNU202100948
論文種類: 學術論文
相關次數: 點閱:87下載:3
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  • 近年來因為抗生素的過度使用導致環境汙染的問題逐漸受到重視。目前在臨床上使用之粘桿菌素colistin 會對人體造成腎毒性及神經毒性等副作用,因此被列為對抗格蘭氏陰性細菌感染的最後一線用藥。在許多國家中粘桿菌素也被大量使用在畜產業上作為動物傳染病的防治,進而導致粘桿菌素隨著動物排泄物及未食用完畢的食物進入水域環境中,產生具有抗藥性的大腸桿菌。然而,粘桿菌素對水生動物可能的危害卻仍未被研究。因此本研究目的是利用斑馬魚胚胎為模式以探討粘桿菌素暴露對魚類可能產生的毒性以及水中離子濃度對其毒性之影響。結果發現斑馬魚胚胎暴露粘桿菌素 96小時之半致死濃度約為3 μM,死亡個體出現皮膚細胞破損現象,但未產生發育異常與畸形;在亞致死濃度下桿菌素會減少側線毛細胞數量以及離子細胞數量,並損害角質細胞結構。 綜合上述 在隨時間的觀察發現 魚體皮膚角質細胞在暴露粘桿菌素後會逐漸破損,最終導致皮膚細胞瓦解,體內離子失衡,魚體死亡。藉由改變水中的離子濃度,發現鈣離子濃度對粘桿菌素的毒性有關鍵性的影響。提高鈣濃度可以有效減低其毒性,降低鈣濃度會提高毒性。本研究證實了粘桿菌素在水域汙染後可能對魚類產生危害,藉由提高水中的鈣離子濃度可減低其毒性。

    In recent years, the problem of environmental pollution caused by the excessive use of antibiotics has gradually attracted attention. In clinical, colistin is listed as the last-line drug to combat Gram-negative bacterial infections due to the side effects such as nephrotoxicity and neurotoxicity to the human. However, colistin has been widely used in the animal industry to prevent and treat animal infectious diseases in many countries. Colistin was found to contaminate water environments and produced drug-resistant Escherichia coli. However, the potential toxicity of colistin to aquatic animals has not been studied yet. The purpose of this study was to use zebrafish embryos as a model to explore the toxicity of colistin. The result showed that the 50% lethal concentration after 96 hrs colistin exposure was about 3 μM. The skin was damaged in the dead individual. However, developmental abnormalities and deformities were not found. Colistin decreased the number of lateral hair cells and ionocytes, and damaged the keratinocytes structure. We found that skin keratinocytes were severely damaged and detached after exposure, leading to hypotonic swelling of the yolk sac, loss of ion contents, cell lysis, and eventual death. We also found that increasing the calcium concentration of water reduced the toxicity of colistin. In conclusion, this study demonstrated that colistin can pose a threat to fishes by impairing skin cells and functions.

    摘要 v Abstract vi 研究背景 1 粘桿菌素Colistin介紹及臨床應用 1 粘桿菌素畜產養殖業之應用 1 粘桿菌素之抗藥性環境危害 2 粘桿菌素對細菌之作用機制 2 粘桿菌素的腎毒性研究 3 粘桿菌素的神經毒性研究 4 抑制粘桿菌素殺菌機制 4 模式動物-斑馬魚 5 毒理模式 5 斑馬魚的表皮功能 6 斑馬魚的離子細胞 6 斑馬魚毛細胞 7 研究目的 8 實驗設計 9 第一部分-粘桿菌素96小時毒性試驗 9 第二部分-粘桿菌素24小時毒性試驗 9 第三部分-不同人工水組成條件下對於粘桿菌素毒性影響 10 第四部分-觀測粘桿菌素與鈣離子含量之毒性相關性 10 實驗流程 11 材料與方法 13 實驗動物 13 粘桿菌素的製備 13 高、低鈣水、高鎂水、高硫酸鈉水及高氯化鈉水的製備 14 斑馬魚仔魚的死亡率及孵化率觀察 15 斑馬魚仔魚的發育相關指標 15 斑馬魚仔魚的活體螢光染色 16 連續攝影測量方法 17 掃描式電子顯微鏡影像觀測(Scanning electron microscopy,SEM)(SU-3500) 18 掃描式離子選擇電極技術(SIET)(NMT, YoungerUSA, Amherst, MA, USA) 18 感應耦合電漿質譜儀(ICP-MS)19 統計數據分析 19 結果21 第一部分-colistin的毒性試驗 21 實驗一:96小時計算斑馬魚的死亡率及孵化率 21 實驗二:96小時偵測斑馬魚的發育毒性 21 實驗三:96小時計算斑馬魚的毛細胞數量及功能 22 實驗四:96小時計算斑馬魚的離子細胞數量 22 實驗五:96小時觀察斑馬魚在電子顯微鏡下的型態 22 第二部分-高濃度colistin 24小時暴露的急毒性試驗 23 實驗六:24小時計算斑馬魚的死亡率 23 實驗七:2小時縮時攝影下觀察斑馬魚的體表狀況 24 實驗八:6小時處理以ICP-MS測量斑馬魚體內離子含量 24 第三部分-不同人工水組成條件下對於粘桿菌素毒性影響 24 實驗九:96小時以CaSO4、MgSO4、Na2SO4、NaCl不同離子組成之人工水對粘桿菌素造成死亡率之影響 24 實驗十:96小時以CaSO4、MgSO4不同離子組成之人工水對粘桿菌素造成毛細胞數目改變之影響 25 第四部分-改變鈣離子濃度加colistin長時間暴露下保護效果 26 實驗十一:96小時計算斑馬魚在NW、高鈣水與低鈣水之死亡率 26 實驗十二:96小時計算斑馬魚在不同離子組成人工水中與粘桿菌素處理的毛細胞數量 26 實驗十三:96小時計算斑馬魚在不同離子組成人工水中與粘桿菌素處理的離子細胞數量 27 實驗十四:96小時觀察斑馬魚在不同離子組成人工水中與粘桿菌素處理之電子顯微鏡下的型態 28 討論 29 粘桿菌素毒性探討 29 高鈣離子保護相關機制 31 24小時實驗濃度及實驗限制 33 MET通道與粘桿菌素毒性的關係 34 離子細胞分析 34 氧化壓力與細胞凋亡路徑分析 35 結論 37 參考資料 38 附圖 46

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