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研究生:游妙娟
研究生(外文):Miao-Chuan Yu
論文名稱:奈米氧化鋅微粒於自發性高血壓大鼠之呼吸毒性研究
論文名稱(外文):Inhalation Toxicity of Ultrafine Zinc Oxide Particles in Spontaneously Hypertensive Rats
指導教授:鄭尊仁鄭尊仁引用關係
指導教授(外文):Tsun-Jen Cheng
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文出版年:2008
畢業學年度:97
語文別:中文
論文頁數:55
中文關鍵詞:奈米氧化鋅呼吸暴露自發性高血壓大鼠肺部灌洗液肺部發炎
外文關鍵詞:ZnO nanoparticleInhalation exposureSpontaneously hypertensive ratBronchoalveolar lavageLung inflammation
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奈米氧化鋅是台灣奈米產業積極發展的產品,常用於如輪胎、塗料、化妝品等,可提高耐磨性、延長使用時間、有效屏敝紫外線等功能,為具有市場潛力的重要產品,因此令人關注的是它們進入人體內是否會影響人類健康。而針對奈米氧化鋅的毒理研究,過去常利用氣管灌注方式進行動物暴露,但因微粒溶於液體中會產生聚集現象,無法掌握微粒實際大小及模擬實際暴露,因此有必要利用呼吸暴露方式確切掌握微粒粒徑及濃度。
本實驗室已進行先趨性的呼吸暴露研究,利用爐管氣流原理產生氧化鋅微粒,但仍有一些缺點需要改進,包括產生器需要長時間才能穩定產生微粒,和無法同時進行暴露組及控制組的暴露,因此無法精確評估所造成的劑量反應。本研究則改良先前奈米氧化鋅產生器及呼吸暴露系統,之後利用此套系統暴露抗氧化能力較差的自發性高血壓大鼠,並以微粒粒徑濃度分佈自動監測儀進行監測,監測暴露微粒的大小及濃度,探討其毒性效應。
微粒產生暴露系統的部份,於微粒產生器及暴露腔之間設計較小的混合腔,減少微粒穩定時間,濃度預估約10分鐘內即可均勻分佈,之後將微粒由混合腔導入全身性暴露腔,其暴露數目濃度可達106 #/cm3、粒徑約12-15 nm。
實驗動物暴露的部份,利用微粒產生暴露系統,經全身性暴露腔對自發性高血壓大鼠進行呼吸暴露,暴露1天6小時(n=6)或1天6小時連續3天(n=6)的奈米氧化鋅為暴露組,並以暴露過濾空氣為對照組(n=6),暴露後3小時採取尾巴靜脈血,並於24小時後進行犧牲採集全血及收集肺泡灌洗液。於全血量測周邊血液血球數目(CBC/DC)和細胞激素TNF-α和IL-6代表系統性發炎;分析肺泡灌洗液中乳酸脫氫酵素(lactate dehydrogenase)和總蛋白質(total protein)代表肺部傷害,並計算總細胞數(total cells)和嗜中性球(neutrophils)代表肺部發炎。
結果發現實驗動物暴露1天後在肺泡灌洗液中,暴露組的嗜中性球比例高於控制組(p<0.05),但暴露3天後嗜中性球比例在暴露組和控制組沒有差異;系統性發炎指標部份,不論暴露1天或連續暴露3天,皆未發現系統性發炎反應;IL-6反應結果同嗜中性球的表現,TNF-α於暴露後任何時間點皆沒有差異。
因此,本研究發現利用奈米氧化鋅微粒產生及暴露系統,暴露自發性高血壓大鼠於低濃度的奈米氧化鋅後,會誘導肺部發炎反應;且持續暴露後可觀察到耐受性表現。
Zinc oxide (ZnO) nanoparticles have been widely used commercially for rubber, paint, and cosmetics. With the advent of nanotechnology, the potential health effects of novel technology have raised concerns. The toxicity of ZnO nanoparticles has been studied using intratracheal instillation. However, the exact particle size was not clear. Thus, inhalation exposure was proposed to overcome this problem.
In our previous inhalation studies, ZnO nanoparticles were produced by a furnace tube airflow system, but there are still some deficiencies. The system took long time to become stable, and the exposure and control groups could not be exposed at the same time. In this study, we improved the ZnO nanoparticle generator and animal exposure system, then we used this device to test the toxicity of ZnO.
For particle generation and exposure system, we designed a smaller mixing chamber between the generator and exposure chamber, and this reduced the time for nanoparticles to become stable. In exposure chamber, particle number concentration reached 106 #/cm3, and geometric mean diameter was about 12-15 nm.
Spontaneously hypertensive rats (SHR) were exposed by this system to assess lung toxicity. SHR were exposed to ZnO nanoparticle in whole body exposure chamber for 1 day (1X, n=6), or for 3 successive days (3X, n=6) for 6 h/day. SHR (n=6) were also exposed to clean filtered air as controls. We collected the tail-blood to analyze the cytokines at 3 h postexposure to ZnO, and sacrificed the animals to obtain the whole blood and perform bronchoalveolar lavage at 24 h postexposure. The whole blood were tested for CBC/DC and cytokines TNF-α and IL-6. The lavage supernatants were analyzed for total protein and lactate dehydrogenase activity for lung injury while total cells and neutrophils were determined for lung inflammation.
The percentage of neutrophils in exposure groups increased significantly as compared to the controls after 1 day of exposure (p<0.05), while there was no difference after 3 days of exposure. Cytokine IL-6 in peripheral blood expression was similar to neutrophils (p<0.05). But the systemic inflammation and TNF-α were not different from controls after 1 day or 3 days exposure.
Our study has demonstrated that ZnO nanoparticles may cause lung inflammation after 1 day of exposure, but not after 3 days of exposure. This suggests lung inflammation tolerance may develop after repeated exposure to ZnO.
目錄 I
奈米氧化鋅微粒於自發性高血壓大鼠之呼吸毒性研究 1
摘要 2
Abstract 4
第一章 前言 6
第二章 文獻探討 7
2-1 奈米粉體--氧化鋅運用 8
2-2 氧化鋅微粒毒理 8
2-2.1 流行病學 9
2-2.2 動物實驗 10
2-3 肺部發炎及傷害指標 11
2-4 系統性發炎指標及細胞激素 12
2-5 奈米氧化鋅產生器 13
第三章 材料方法 15
3-1 微粒產生及暴露 15
3-2 研究設計 15
3-3 研究架構 16
3-4 實驗動物 16
3-5 生化指標 16
3-5.1 全身性發炎-周邊血液血球分析 16
3-5.2 肺泡發炎及損傷-肺泡灌洗液指標分析 17
3-6 統計分析方法 18
第四章 研究結果 19
4-1微粒產生暴露系統 19
4-2 動物實驗 20
第五章 討論 22
5-1 產生器及暴露系統 22
5-2 肺部毒性 23
第六章 參考文獻 28

表目錄 35
表1 比較改良前後之結果 35
表2 暴露3天不同的平均濃度及幾何平均粒徑 36
表3 實驗動物的基本特性 37
表4 暴露1天後肺泡灌洗液指標分析 38
表5 暴露3天後肺泡灌洗液指標分析 38
表6 暴露1天後系統性發炎反應指標測定 39
表7 暴露3天後系統性發炎反應指標測定 39
表8 暴露1天後TNF-α測定 40
表9 暴露3天後TNF-α測定 40
表10 暴露1天後IL-6測定 41
表11 暴露3天後IL-6測定 41

圖目錄 42
圖1(A) 微粒產生暴露系統原始圖 42
圖1(B) 微粒產生暴露系統流程原始圖 42
圖2 原始系統-數目濃度時間分佈圖 43
圖3 原始系統-粒徑時間分佈圖 43
圖4 微粒產生混合腔系統示意圖 44
圖5 微粒產生全身暴露系統示意圖 45
圖6 微粒產生全身性暴露系統 45
圖7 改良後-數目濃度時間分佈圖 46
圖8 改良後-粒徑時間分佈圖 46
圖9 微粒產生全身性暴露系統(NYU) 47
圖10 全身性暴露腔-四個孔洞測試 47
圖11 全身性暴露腔-粒徑與數目濃度分佈圖 47
圖12 暴露3天粒徑與數目濃度分佈圖 48
圖13 全身性暴露腔-數目濃度時間分佈圖 49
圖14 全身性暴露腔-粒徑時間分佈圖 49
圖15(A) 肺泡灌洗液中總細胞數(A)和嗜中性球(B) 50
圖15(B) 肺泡灌洗液中乳酸脫氫酶(C)和總白質量(D) 50
圖16(A) 周邊血液中紅血球(A)和白血球(B) 51
圖16(B) 周邊血液中血小板(C)和血紅蛋白(D) 51
圖17(A) 細胞激素TNF-α暴露1天(A)和暴露3天(B)濃度值 52
圖17(B) 細胞激素IL-6暴露1天(C)和暴露3天(D)濃度值 52

附錄:鼻部暴露腔系統 53
一、鼻腔暴露腔系統開發 53
二、產生暴露系統建置及測試 54
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