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研究生:阮泓慈
研究生(外文):Hung-Tzu Juan
論文名稱:1. 奈米氧化鋅大鼠肺部毒性研究: 鋅離子角色之探討2. 奈米氧化鋅亞慢性呼吸暴露研究
論文名稱(外文):1.Lung Toxicity with Zinc Oxide Nanoparticles: Study of Zinc Ion2.Subchronic Toxicity of Zinc Oxide Nanoparticles by Inhalation in Rats
指導教授:鄭尊仁鄭尊仁引用關係
口試委員:吳焜裕林嬪嬪蕭大智
口試日期:2011-07-11
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:2011
畢業學年度:99
語文別:中文
論文頁數:101
中文關鍵詞:奈米氧化鋅微粒鋅離子氣管灌注肺泡灌洗液肺部發炎蒸發/冷凝法呼吸暴露
外文關鍵詞:zinc oxide nanparticleszinc ionintratracheal instillationbronchoalveolar lavage fluidlung inflammationsubchronic exposure
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part1
奈米氧化鋅為新型的無機材料,被應用於陶瓷、化工、光學、化妝品、藥品以及農藥等領域。目前關於奈米氧化鋅的呼吸毒理學研究仍著重於粒徑大小與毒理作用間的探討。奈米氧化鋅本身為可溶性物質,其造成的累積毒性與溶解於動物體內所產生的鋅離子是否會對於毒性造成影響目前尚未釐清,因此有必要做更進一步的研究。
過去已有許多鋅離子的偵測方法,但如何分離奈米氧化鋅溶液中氧化鋅微粒與鋅離子,進而偵測鋅離子含量,則是本次實驗亟欲開發的偵測方法,本實驗根據史托克定律計算微粒於流體中所受力之大小推算出離心力大小,成功分離奈米氧化鋅溶液中氧化鋅微粒與鋅離子。並利用該方法進一步分析實驗動物肺泡灌洗液中總鋅以及鋅離子濃度,探討暴露後大鼠之肺部毒性效應。
本研究配製濃度為10mg/ml的奈米氧化鋅溶液,以氣管灌注的方式令健康大鼠暴露奈米氧化鋅,將實驗動物分為五組,分別為暴露後6小時犧牲 (暴露組-1, n=6)、 暴露後24小時犧牲 (暴露組-2, n=6), 暴露後48小時犧牲 (暴露組-3, n=6)、暴露後72小時犧牲 (暴露組-4, n=6)以及控制組 (氣管灌注PBS, n=8)。並偵測急性暴露肺泡灌洗液後總鋅含量與鋅離子含量,探討與肺部發炎反應間的相關性。
結果發現,在大鼠肺中鋅離子與總鋅濃度呈現正相關的趨勢 (r=0.98),隨著暴露後時間的增加兩者濃度皆有上升,且總鋅濃度 (77.08±127.56 μg/L)與鋅離子濃度 (31.72±67.61 μg/L)皆於暴露後48小時達到最大值,接著有恢復的情況。暴露組的嗜中性球百分比、總細胞數、總蛋白質亦於暴露後48小時達到最大值並顯著高於控制組 (p<0.05),在暴露後72小時有下降,與總鋅、鋅離子濃度有相同的趨勢。系統性發炎指標的部分不論暴露後6, 24, 48或72小時犧牲,皆未發現系統性發炎反應。
奈米氧化鋅暴露後於動物體內有二次流布的情形,本研究僅偵測肺泡灌洗液內的奈米氧化鋅微粒濃度,未考慮殘留於肺組織或巨噬細胞內的微粒,並無法有
效探討鋅離子所扮演的角色,為本次研究限制。本研究首度嘗詴於不同時間點偵測其發炎反應,並與其總鋅含量與鋅離子含量做比較,發現暴露後48小時其發炎反應與鋅濃度具相關性。其機制可能與暴露後48小時微粒已自細胞中釋出,故該時間點肺泡灌洗液內濃度較可反應真實狀況有關,但相關機轉仍需進一步研究證明。
part2
奈米氧化鋅為新型的無機材料,被應用於陶瓷、化工、光學、化妝品、藥品以及農藥等領域,雖已有許多研究證實奈米氧化鋅之毒性,但目前關於奈米氧化鋅的呼吸毒理學研究仍著重於急性毒性作用探討。奈米氧化鋅本身為可溶性物質,其進入動物體後是否會持續的累積並產生毒性,目前尚未釐清,因此有必要對奈米氧化鋅進入動物體內之亞慢性毒性作用更進一步的研究。
本實驗室過去已利用蒸發/冷凝法產生奈米氧化鋅微粒進行急性呼吸暴露研究,而本研究利用這套系統進行亞慢性呼吸暴露,將大鼠置於全身性暴露腔內暴露於奈米氧化鋅下兩周 (5小時/天、5天/周)。實驗動物分為六組,分別為暴露後1天犧牲 (暴露組-5;n=6、控制組-5;n=4)、暴露後7天犧牲 (暴露組-6;n=6、控制組-6;n=4)、暴露後30天犧牲 (暴露組-7;n=6、控制組-7;n=4),其中控制組為吸入奈米產生器經HEPA過濾之乾淨空氣。犧牲後採集血液樣本分析全血中的血球數目、以及血清中的乳酸脫氫酵素以及總蛋白質含量的分析,並採集肺泡灌洗液進行肺部傷害指標分析,包含總細胞數、嗜中性球、乳酸脫氫酵素、總蛋白質含量的分析以及肺部組織病理檢驗。
本研究使實驗動物暴露於2.66×06顆/立方公分,粒徑為51.47 nm的奈米氧化鋅下,發現經過兩周的連續暴露後24小時,暴露組體重 (313.33±16.33g)顯著低於控制組 (350±24.49g),且伴隨著總細胞數 (3.47×105±6.02×104)、嗜中性球比率 (31.92±8.96%)、總蛋白質 (0.52± 0.13 mg/ml)的上升,代表仍有急性發炎反應發生,而該發炎反應可於暴露後30天完全回復,在組織病理部分亦有相同的結果。
目前已有許多奈米微粒產生方法,而本研究可成功的在暴露的兩周內維持單一粒徑且高濃度的奈米氧化鋅產生,故可首度探討奈米氧化鋅之亞慢性毒理反應。而健康大鼠連續暴露奈米氧化鋅兩周後,發現其肺部急性發炎反應仍持續,與過去研究中發現暴露後會產生耐受性的結果不同。於暴露後7天發炎指標比起控制組有下降的趨勢,到了暴露後30天與控制組已無顯著差異,顯示暴露奈米氧化鋅產生的發炎為可恢復性反應。
本研究為奈米氧化鋅長時間連續暴露之先驅研究,由於目前仍無奈米氧化鋅長期連續暴露相關研究,故先以較大劑量觀察其不良健康效應,但高濃度的暴露無法反應實際情況為本次研究限制。本研究發現經過兩周的連續暴露後,實驗動物仍有急性發炎反應,且發炎反應可於暴露後30天回復。而暴露後造成的長期不良影響,需組織病理更進一步的探討,以釐清相關機制。

part1
Zinc oxide nanoparticles have been widely used in the manufacturing for ceramics, chemicals, cosmetics, pharmaceuticals and pesticides. Previous studies have shown that the toxicity of non-soluble nanoparticles is linked with particle size and surface area. Zinc oxide nanoparticls can be dissolved in liquid and the toxicity is resulted from zinc ions in in vitro studies. However, it is not clear about the role of zinc ion in animal studies.
Several methods to detect zinc ions have been used, but yet not clearly validated. In this study, we developed a centrifugation method to separate zinc ion and zinc oxide nanoparticles. Subsequently, we used this method to investigate the association between total zinc level, zinc ion level and lung inflammation in bronchoalveolar lavage fluid (BALF) in SD rats treated with zinc oxide nanoparticles.
SD rats were exposed to zinc oxide nanoparticles with intratracheal instillation (10mg/ml) then sacrificed ar 6 hr (exposure-1, n=6), 24 hr (exposure-2, n=6), 48 hr (exposure-3, n=6), and 72 hr (exposure-4, n=6). PBS was used as controls (control, n=8). We collected bronchoalveolar lavage fluid and peripheral blood to analysis the lung inflammation markers, total number of cells, proportion of neutrophils, total zinc and zinc ion level to investigate the association between zinc level and lung inflammations.
We found total zinc levels were highly associated with zinc ion level (r=0.98). Both total zinc (77.08±127.56 μg/L) and zinc ion (31.72±67.61 μg/L) had a peak level at 48 hr post-exposure. The inflammation markers level also reached the maximum level at 48 hr post-exposure (p<0.05) then decreased at 72 hr. But systemic inflammations were not increased after exposure.
Our results suggest zinc oxide nanoparticles may relocate after exposure into lung parenchymal tissue then reenter into the luminal side of the airway. The limitation of our study is that only BALF was used to determine the zinc levels. This may explain why we only detect an association between zinc levels and lung inflammation at 48 hr. This pioneer study shed some light on the complicated issues about the toxicity of zinc oxide nanoparticles in animals. Further studies are needed to elucidate the exact toxicological mechanism of zinc oxide nanoparticles.
part2
Zinc oxide nanoparticles have been widely used in the manufacturing for ceramics, chemicals, cosmetics, pharmaceuticals and pesticides. In previous studies, the acute toxicity of zinc oxide nanoparticles has been investigated. However, the data about subchronic toxicity for zinc oxide nanopaticles were limited.
Our lab has successfully constructed a nanopaticle generation system and exposed animals for acute toxicity. In this study, we used this system to investigate the zinc oxide subchronic toxicity on lung inflammation and injuries. The SD rats were exposed for 2 weeks (5 hr/day, 5 day/week) then sacrificed at 1 day (exposure-5, n=6;control-5, n=4), 7 day (exposure-6, n=6;control-6, n=4), and 30 day (exposure-7, n=6;control-7, n=4). We collected bronchoalveolar lavage to determine the lung inflammation including total number of cells, proportion of neutrophils and protein. Histopathological examination was also performed.
Zinc oxide nanoparticles were produced in a furnace system and SMPS was used to monitor the size and number concentrations of particles. The average concentration during exposure was 51.47nm at 2.66×106 particle/cm3. The inflammation markers including netrophils% (31.92±8.96%), total cells (3.47×105±6.02×104) and total protein (0.52± 0.13 mg/ml) at 24 hr post-exposure increased significantly as compared to the control group (p<0.05). The inflammation decreased at 7 days then become no difference from the control group.
In this study, we have performed a subchronic inhalation studies with high concentrations and mono-dispersed zinc oxide nanoparticles. An acute but reversible inflammatory were observed. Further histological studies are needed to assess the subchronic toxicity of zinc oxide nanoparticles.

part1
摘要 ................................................................................................................................. ii
Abstract ............................................................................................................................ iv
目錄 ................................................................................................................................ vi
表目錄 ........................................................................................................................... viii
圖目錄 ............................................................................................................................. ix
第一章 前言 .................................................................................................................... 1
第二章 背景與重要性 .................................................................................................... 2
2.1 奈米微粒特性與毒性 .................................................................................. 2
2.2 奈米氧化鋅微粒 .......................................................................................... 3
2.2.1 微粒特性 .......................................................................................... 3
2.2.2 流行病學研究 .................................................................................. 3
2.2.3 毒理研究 .......................................................................................... 4
2.3 鋅離子 .......................................................................................................... 5
2.3.1 鋅離子偵測 ...................................................................................... 7
2.4 氣管灌注 ...................................................................................................... 8
2.4.1. 奈米微粒溶液製備 .......................................................................... 8
2.5 肺部發炎與傷害指標 .................................................................................. 9
2.6 研究目的 .................................................................................................... 10
第三章 材料與方法 ....................................................................................................... 11
3.1 研究架構 ..................................................................................................... 11
3.2 研究設計 .................................................................................................... 12
3.3 實驗動物 .................................................................................................... 12
3.3.1 動物麻醉與犧牲 ............................................................................ 12
vii
3.4 氣管灌注 .................................................................................................... 12
3.4.1 奈米氧化鋅溶液製備 .................................................................... 13
3.4.2 微粒特性評估與量測 .................................................................... 13
3.4.3 鋅離子量測 .................................................................................... 14
3.5 肺部傷害分析 ............................................................................................ 15
3.6 周邊血液血球分析 .................................................................................... 15
3.7 統計分析 .................................................................................................... 15
第四章 結果 .................................................................................................................. 17
4.1 奈米氧化鋅溶液 ........................................................................................ 17
4.2 鋅離子偵測 ................................................................................................ 18
4.3 動物實驗 .................................................................................................... 18
4.3.1 實驗動物基本特性 ........................................................................ 18
4.3.2 肺部發炎指標 ................................................................................ 18
4.3.3 周邊血液血球指標 ........................................................................ 19
4.3.4 肺中鋅濃度 .................................................................................... 20
第五章 討論 .................................................................................................................. 21
5.1 奈米氧化鋅溶液製備 ................................................................................ 21
5.2 鋅離子偵測 ................................................................................................ 22
5.3 毒性作用分析 ............................................................................................ 23
5.4 總鋅濃度與鋅離子濃度 ............................................................................ 24
5.4.1 微粒二次流布 (Relocation) .......................................................... 25
5.5 結論 ............................................................................................................ 27
第六章 參考文獻 .......................................................................................................... 29
part2
摘要 ................................................................................................................................ xi
Abstract .......................................................................................................................... xiii
目錄 ............................................................................................................................... xv
表目錄 .......................................................................................................................... xvii
圖目錄 ......................................................................................................................... xviii
第一章 前言 .................................................................................................................. 57
第二章 背景與重要性 .................................................................................................. 58
2.1 奈米微粒特性與毒性 ................................................................................ 58
2.2 奈米氧化鋅微粒 ........................................................................................ 59
2.2.1 微粒特性 ........................................................................................ 59
2.2.2 流行病學研究 ................................................................................ 59
2.2.3 毒理研究 ........................................................................................ 60
2.2.4 呼吸毒理 ........................................................................................ 61
2.3 奈米氧化鋅產生器 .................................................................................... 62
2.4 肺部發炎與傷害指標 ................................................................................ 63
2.5 研究目的 .................................................................................................... 63
第三章 材料與方法 ...................................................................................................... 65
3.1 研究架構 .................................................................................................... 65
3.2 研究設計 .................................................................................................... 66
3.3 實驗動物 .................................................................................................... 66
3.3.1 動物麻醉與犧牲 ............................................................................ 66
3.4 全身性呼吸暴露 ........................................................................................ 66
4.3.1 微粒特性量測 ................................................................................ 67
xvi
3.5 肺部傷害分析 ............................................................................................ 68
3.6 周邊血液血球分析 .................................................................................... 68
3.7 統計分析 .................................................................................................... 69
第四章 結果 .................................................................................................................. 70
4.1 微粒產生暴露系統 .................................................................................... 70
4.1.1 微粒特性 ........................................................................................ 70
4.2 實驗動物基本特性 .................................................................................... 70
4.3 肺部發炎指標 ............................................................................................ 71
4.4 周邊血液血球指標 .................................................................................... 71
4.5 組織病理切片 ............................................................................................ 72
第五章 討論 .................................................................................................................. 73
5.1 奈米微粒產生及暴露系統 ........................................................................ 73
5.2 肺部發炎及傷害指標 ................................................................................ 74
5.2.1 耐受性 ............................................................................................ 75
5.2.2 可恢復性 ........................................................................................ 76
5.2 周邊血球及生化指標 ................................................................................ 77
5.2.1 血液生化指標 ................................................................................ 77
5.2.2 血球計數 ........................................................................................ 78
5.3 組織病理切片 ............................................................................................ 79
5.4 結論 ............................................................................................................ 80
第六章 參考文獻 .......................................................................................................... 81

part1
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20. Beckett W. S., Chalupa D. F., Pauly-Brown A., Speers D. M., Stewart J. C., Frampton M. W., Utell M. J., Huang L. S., Cox C., Zareba W., and Oberdorster G., Comparing inhaled ultrafine versus fine zinc oxide particles in healthy adults: a human inhalation study. Am J Respir Crit Care Med, 2005. 171(10): p. 1129-35.
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31
23. Kuschner W. G., D''Alessandro A., Wong H., and Blanc P. D., Early pulmonary cytokine responses to zinc oxide fume inhalation. Environ Res, 1997. 75(1): p. 7-11.
24. Applerot G., Lipovsky A., Dror R., Perkas N., Nitzan Y., Lubart R., and Gedanken A., Enhanced Antibacterial Activity of Nanocrystalline ZnO Due to Increased ROS-Mediated Cell Injury. Advanced Functional Materials, 2009. 19(6): p. 842-852.
25. Xia T., Kovochich M., Liong M., Madler L., Gilbert B., Shi H., Yeh J. I., Zink J. I., and Nel A. E., Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano, 2008. 2(10): p. 2121-34.
26. Huang C. C., Aronstam R. S., Chen D. R., and Huang Y. W., Oxidative stress, calcium homeostasis, and altered gene expression in human lung epithelial cells exposed to ZnO nanoparticles. Toxicol In Vitro, 2010. 24(1): p. 45-55.
27. Wang B., Feng W. Y., Wang M., Wang T. C., Gu Y. Q., Zhu M. T., Ouyang H., Shi J. W., Zhang F., Zhao Y. L., Chai Z. F., Wang H. F., and Wang J., Acute toxicological impact of nano- and submicro-scaled zinc oxide powder on healthy adult mice. Journal of Nanoparticle Research, 2008. 10(2): p. 263-276.
28. Chen J. K., Shih M. H., Peir J. J., Liu C. H., Chou F. I., Lai W. H., Chang L. W., Lin P. P., Wang M. Y., Yang M. H., and Yang C. S., The use of radioactive zinc oxide nanoparticles in determination of their tissue concentrations following intravenous administration in mice. Analyst, 2010. 135(7): p. 1742-1746.
29. Conner M. W., Flood W. H., Rogers A. E., and Amdur M. O., Lung injury in guinea pigs caused by multiple exposures to ultrafine zinc oxide: changes in pulmonary lavage fluid. J Toxicol Environ Health, 1988. 25(1): p. 57-69.
30. Hirano S., Higo S., Tsukamoto N., Kobayashi E., and Suzuki K. T., Pulmonary Clearance and Toxicity of Zinc-Oxide Instilled into the Rat Lung. Archives of Toxicology, 1989. 63(4): p. 336-342.
31. Sayes C. M., Reed K. L., and Warheit D. B., Assessing toxicity of fine and nanoparticles: Comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicological Sciences, 2007. 97(1): p. 163-180.
32. Sung J. H., Choi B. G., Maeng S. H., Kim S. J., Chung Y. H., Han J. H., Song K. S., Lee Y. H., Cho Y. B., Cho M. H., Kim K. J., Hyun J. S., and Yu I. J., Recovery from welding-fume-exposure-induced lung fibrosis and pulmonary function changes in sprague dawley rats. Toxicol Sci, 2004. 82(2): p. 608-13.
33. Gordon T., Chen L. C., Fine J. M., Schlesinger R. B., Su W. Y., Kimmel T. A., and Amdur M. O., Pulmonary effects of inhaled zinc oxide in human subjects, guinea pigs, rats, and rabbits. Am Ind Hyg Assoc J, 1992. 53(8): p. 503-9.
32
34. Sensi S. L., Yin H. Z., Carriedo S. G., Rao S. S., and Weiss J. H., Preferential Zn2+ influx through Ca2+-permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proceedings of the National Academy of Sciences of the United States of America, 1999. 96(5): p. 2414-2419.
35. Gazaryan I. G., Krasinskaya I. P., Kristal B. S., and Brown A. M., Zinc irreversibly damages major enzymes of energy production and antioxidant defense prior to mitochondrial permeability transition. J Biol Chem, 2007. 282(33): p. 24373-80.
36. Kim Y. M., Reed W., Wu W., Bromberg P. A., Graves L. M., and Samet J. M., Zn2+-induced IL-8 expression involves AP-1, JNK, and ERK activities in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol, 2006. 290(5): p. L1028-35.
37. Yang Z. H. and Xie C. S., Zn2+ release from zinc and zinc oxide particles in simulated uterine solution. Colloids and Surfaces B-Biointerfaces, 2006. 47(2): p. 140-145.
38. Wong S. W. Y., Leung P. T. Y., Djurisic A. B., and Leung K. M. Y., Toxicities of nano zinc oxide to five marine organisms: influences of aggregate size and ion solubility. Analytical and Bioanalytical Chemistry, 2010. 396(2): p. 609-618.
39. Franklin N. M., Rogers N. J., Apte S. C., Batley G. E., Gadd G. E., and Casey P. S., Comparative toxicity of nanoparticulate ZnO, bulk ZnO, and ZnCl2 to a freshwater microalga (Pseudokirchneriella subcapitata): the importance of particle solubility. Environ Sci Technol, 2007. 41(24): p. 8484-90.
40. Lin D. and Xing B., Root uptake and phytotoxicity of ZnO nanoparticles. Environ Sci Technol, 2008. 42(15): p. 5580-5.
41. Lin W. S., Xu Y., Huang C. C., Ma Y. F., Shannon K. B., Chen D. R., and Huang Y. W., Toxicity of nano- and micro-sized ZnO particles in human lung epithelial cells. Journal of Nanoparticle Research, 2009. 11(1): p. 25-39.
42. Bai W., Zhang Z. Y., Tian W. J., He X., Ma Y. H., Zhao Y. L., and Chai Z. F., Toxicity of zinc oxide nanoparticles to zebrafish embryo: a physicochemical study of toxicity mechanism. Journal of Nanoparticle Research, 2010. 12(5): p. 1645-1654.
43. Deng X., Luan Q., Chen W., Wang Y., Wu M., Zhang H., and Jiao Z., Nanosized zinc oxide particles induce neural stem cell apoptosis. Nanotechnology, 2009. 20(11): p. 115101.
44. Pipan-Tkalec Z., Drobne D., Jemec A., Romih T., Zidar P., and Bele M., Zinc bioaccumulation in a terrestrial invertebrate fed a diet treated with particulate ZnO or ZnCl2 solution. Toxicology, 2010. 269(2-3): p. 198-203.
33
45. Kaegi R., Wagner T., Hetzer B., Sinnet B., Tzuetkov G., and Boller M., Size, number and chemical composition of nanosized particles in drinking water determined by analytical microscopy and LIBD. Water Research, 2008. 42(10-11): p. 2778-2786.
46. Brain J. D., Knudson D. E., Sorokin S. P., and Davis M. A., Pulmonary distribution of particles given by intratracheal instillation or by aerosol inhalation. Environ Res, 1976. 11(1): p. 13-33.
47. Leong B. K., Coombs J. K., Sabaitis C. P., Rop D. A., and Aaron C. S., Quantitative morphometric analysis of pulmonary deposition of aerosol particles inhaled via intratracheal nebulization, intratracheal instillation or nose-only inhalation in rats. J Appl Toxicol, 1998. 18(2): p. 149-60.
48. Warheit D. B., Sayes C. M., and Reed K. L., Nanoscale and Fine Zinc Oxide Particles: Can in Vitro Assays Accurately Forecast Lung Hazards following Inhalation Exposures? Environmental Science & Technology, 2009. 43(20): p. 7939-7945.
49. Gupta S., Pandey D., Misra V., and Viswanathan P. N., Effect of Intratracheal Injection of Zinc-Oxide Dust in Guinea-Pigs. Toxicology, 1986. 38(2): p. 197-202.
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