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研究生:鄭進裕
研究生(外文):Chin-Yu Cheng
論文名稱:銅離子對斑馬魚畸胎及胚胎發育毒理機制探討
論文名稱(外文):The effects of copper on the teratogenesis and toxicological mechanism in the development of zebrafish( Danio rerio) embryos
指導教授:耿全福
指導教授(外文):Chuian-Fu Ken
學位類別:碩士
校院名稱:國立彰化師範大學
系所名稱:生物技術研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:168
中文關鍵詞:銅離子氧化壓力抗氧化酵素基因表現畸胎毒理機制
外文關鍵詞:copperoxidative stressantioxidant enzymesgene expressionteratogenesistoxicological mechanism
相關次數:
  • 被引用被引用:1
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  • 收藏至我的研究室書目清單書目收藏:1
銅為生物體內必須之微量元素,但暴露在過多銅離子污染下,會造成魚體的病理反應。本研究分析銅離子對斑馬魚胚胎所造成的畸胎毒性影響及探討其毒理分子作用機制。我們以2.5, 5和10 ppm 的一價或二價銅離子處理斑馬魚胚胎至48小時,結果造成胚胎發育遲緩、不全、卵黃吸收力降低及心臟跳動速率增加等病理現象,胚胎活存率下降,畸胎形成率顯著增加,LC 50均為5 ppm。利用2',7'-二氯螢光乙酞乙酸鹽分析證實在2.5至10 ppm一價或二價銅離子處理後,胚胎內ROS有明顯增加。蛋白質carbonylation及脂質過氧化指標有增加趨勢,證實銅離子會造成胚胎氧化損傷,導致畸胎形成。利用Real-time RT-PCR分析各抗氧化酵素基因表現情形。包括Cu/Zn-SOD、Mn-SOD、Catalase、peroxiredoxin-2及peroxiredoxin-6基因,在二價銅處理6小時後表現都有增加趨勢,處理48小時後則Mn-SOD, peroxiredoxin-2及peroxiredoxin-6基因表現均受到抑制。利用啟動子分析證實轉錄因子MTF-1的結合位MRE在銅所誘導Mn-SOD 基因表現過程中扮演重要角色。此外我們將斑馬魚Mn-SOD基因表現knock down後發現,胚胎的ROS顯著增加,且胚胎心臟有心胞膜肥大,心臟萎縮,尾巴彎曲及體型發育不全等現象產生,並且增加銅所誘導脂質過氧化損傷。顯示Mn-SOD對胚胎發育與氧化逆境適應是必須且重要的。
Copper (Cu) is an essential trace element for all organisms, but excess copper exposure can exert a variety of pathological effects in fish. In this study, we treated zebrafish embryos with 2.5-10 ppm either Cu+ or Cu ++ for 48h, survival rate was decreased and abnormal embryos was increased significantly. Lethal Concentration Fifty (LC50) was 5 ppm for either Cu+ or Cu++ treated. Reactive oxygen species (ROS) of embryos under copper ions treated were elevated by DCFH-DA analysis. The levels of protein carbonylation and lipid peroxidation were increased significantly after Cu++ treatment. We have evaluated the five antioxidant enzyme gene expression under 5 ppm copper treated by Real-time RT-PCR. The results showed that the expressions of Cu/Zn-SOD, Mn-SOD, Catalase, peroxiredoxin 2 and peroxiredoxin 6 gene were increased at 6 h, but Mn-SOD, peroxiredoxin 1 and peroxiredoxin 6 decreased at 48 h. In Mn-SOD promoter assays, we identified that MTF-1 was an important transcription factor to Mn-SOD gene expression under copper treated. Using morpholino to knock down Mn-SOD gene expression at one-cell stage of embryonic development, the embryo’s ROS and lipid peroxidation were increased the teratogenesis, especially at heart failure. The results showed that Mn-SOD was important for zebrafish embryonic development and oxidative stress resist.
第一章:前言 1
第一節: 重 金 屬 銅(Copper)介紹 1
1-1 銅分佈 1
1-2 銅正常河川湖泊含量值 1
1-3 銅生理所需含量介紹 1
1-4 銅的吸收 2
1-5 MTF-1(Metal-responsive transcription factor-1) 5
1-6 過量銅如何造成細胞傷害 5
1-7 銅所誘導魚類細胞死亡 6
1-8 環境污染對水生生物毒性研究 7
1-9 銅與人類相關的疾病 7
第二節: 畸 胎 介 紹 (teratogenesis) 8
2-1 何謂畸胎 8
2-2 畸胎生化及分子機制 9
第三節: 活 性 氧 分 子 Reactive oxygen species (ROS) 9
3-1 何謂ROS? 9
3-2 細胞內如何產生ROS 9
3-3 ROS造成細胞傷害 10
3-3-1脂質過氧化(lipid peroxidation)生物指標 11
3-3-2 蛋白質Protein carbonyl 損傷指標 12
3-3-3 DNA 損傷生物指標 13
第四節 抗 氧 化 系 統 14
4-1 超氧歧化酶(SOD) 15
4-1-1 銅鋅型超氧歧化酶(Cu/Zn-SOD) 15
4-1-2 錳型超氧歧化酶(Mn-SOD) 16
4-2 過氧化氫酶(Catalase) 21
4-3 peroxiredoxin (Prx) 22
4-4 Glutathione peroxidases (GPx) 24
第五節: 斑 馬 魚 介 紹 25
第六節: 研 究 動 機 25
第二章: 實 驗 材 料 28
第三章: 實 驗 方 法 41
3-1斑馬魚飼養與交配產卵 41
3-2抽取斑馬魚RNA 41
3-3合成cDNA 41
3-4 銅(copper)毒物分析 42
3-4.1 配製銅離子溶液 42
3-4.2 不同濃度Cu+及Cu++對斑馬魚胚胎存活率分析 42
3-4.3胚胎銅含量分析 43
3-4.4 2', 7'-dichlorofluorescin diacetate (DCFH-DA) 分析胚胎細胞內ROS 43
3-4.5 Lipid Hydroperoxide 分析 43
3-4.6 Protein carbonyl 分析 44
3-4.7 RT-PCR分析胚胎抗氧化酵素mRNA表現46
3-4.8 DNA膠片之配製及DNA 電泳 47
3-4.9 Real-time RT-PCR分析胚胎抗氧化酵素mRNA表現 47
3-5基因構築 50
3-5.1 Mn-SOD 啟動子(Promoter) 構築 50
3-5.1.1 Mn-SOD啟動子選殖至pEGFP-1 載體上 50
3-5.1.2 DNA 電泳 51
3-5.1.3 DNA 萃取 51
3-5.1.4 DNA ligation 反應 52
3-5.1.5 勝任細胞(TOP10)製備 52
3-5.1.6 Transformation作用 52
3-5.1.7抽質體DNA 53
3-5.1.8切酵素確認DNA有接合至選殖載體上 54
3-5.2 Mn-SOD啟動子構築至pGL3.0 basic載體上 54
3-5.3 Mn-SOD 啟動子含MRE結合位片段構築 57
3-5.4 Mn-SOD基因構築至真核表現載體 60
3-5.5 Foxo5基因單一位置突變構築 62
3-6中量DNA抽取 65
3-7顯微注射 66
3-7.1 pEGFP-1-Mn-SOD啟動子表現分析 66
3-7.2斑馬魚Mn-SOD啟動子強度分析 67
3-7.3 pCGR3.0-Mn-SOD表現分析 68
3-7.4 pDsRed-C1 monomer-foxo5表現分析 69
3-8 Dual-Luciferase 分析 70
3-8.1 Mn-SOD啟動子基礎表現分析 70
3-8.2 銅離子對Mn-SOD基因啟動子之調控分析 70
3-9 Morpholino微注射 70
3-10酵素活性分析 71
3-10.1胚胎Mn-SOD活性分析 71
3-11 蛋白質的濃度測定 72
3-12 Whole-Mount in situ hybridization核酸雜交 73
3-13成魚組織Cu/ZnSOD, Mn-SOD mRNA分析 77
3-14繪圖與統計分析 78
第四章: 結 果 79
壹.觀察銅所誘導斑馬魚畸胎 79
貳.銅所誘導胚胎ROS及氧化壓力損傷 81
叄.銅處理斑馬魚胚胎後分析抗氧化酵素基因之轉錄表現 84
肆.斑馬魚Mn-SOD啟動子分析 85
伍. total-SOD活性分析 87
陸.Mn-SOD 基因表現knock down後斑馬魚胚胎發育觀察 87
柒.斑馬魚胚胎及成魚各組織的Mn-SOD mRNA表現 89
捌.斑馬魚Mn-SOD EGFP之啟動子表現 91
第五章: 討 論 92
壹.銅離子對斑馬魚致死之影響 92
貳.銅離子對胚胎發育影響 93
叄.銅離子造成斑馬魚胚胎生物累積傷害 94
肆.銅處理下對於斑馬魚胚胎抗氧化酵素mRNA表現量的影響 96
伍.銅處理下對於斑馬魚胚胎SOD抗氧化酵素活性的影響 97
陸. Mn-SOD 啟動子分析 98
柒.降低斑馬魚胚胎中Mn-SOD活性表現及銅離子所誘導胚胎損傷影響 100
捌.Mn-SOD基因在斑馬魚胚胎發育期間的表現情形 101
玖.Mn-SOD組織表現 102
拾.銅離子所誘導訊息傳遞 103
拾壹.總結 104
拾貳.未來展望 105
第六章: 參 考 文 獻 106
第七章: 結 果 圖 117
第八章: 附 錄 153
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