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研究生：	毛彬旭 Mao, Bin-Hsu
論文名稱：	建立結合細胞、電腦模擬及果蠅實驗之替代測試平台來探討奈米銀誘發毒性之細胞與分子機轉 Establishing an alternative testing platform combining in vitro, in silico and Drosophila-based approaches to explore the cellular and molecular basis of AgNPs-induced toxicity
指導教授：	王應然 Wang, Ying-Jan
共同指導教授:	顏賢章 Yan, Shian-Jang
學位類別：	博士 Doctor
系所名稱：	醫學院 - 環境醫學研究所 Department of Environmental and Occupational Health
論文出版年：	2021
畢業學年度：	109
語文別：	英文
論文頁數：	117
中文關鍵詞：	奈米銀、替代性測試策略、果蠅、資料庫知識探索、決策樹、細胞凋亡、自噬作用、細胞週期休止、胰臟炎、DNA損傷、Nrf2-依賴抗氧化途徑、TRAP1蛋白
外文關鍵詞：	silver nanoparticles, alternative testing strategies, Drosophila melanogaster, knowledge discovery in database, decision tree, apoptosis, autophagy, cell cycle arrest, pancreatitis, DNA damage, Nrf2-dependent antioxidant pathway, TRAP1
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查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

奈米科技產業的蓬勃發展已讓奈米毒理學與奈米危害風險評估兩個領域並進發展。哺乳動物模式已被廣泛應用於測定化學物的暴露對人類與環境可能造成的危害效應，然而在過去的數十年間使用這些活體檢測平台卻因為道德倫理上的考量而備受批評。全球都在呼籲要建立可靠的、能替代哺乳動物模式的檢測方法。雖然許多替代測試策略(例如：體外試驗與電腦模擬方法以及使用非哺乳動物模式)已經被快速地發展出來，但人造奈米微粒所具有的獨特物理化學特性，卻為其發展帶出不同於傳統化學物的考量，即要根據奈米化後所產生的新條件來改善這些測試法。

奈米銀被認為是一把兩刃的利劍，取決於本身的物理化學特性(主要為粒徑大小與表面修飾的種類)而讓其在應用上呈現出不同的利弊影響。然而，關於奈米銀的粒徑與表面修飾的種類對其所引發之危害效應上所扮演的角色，這類體外與體內的機轉研究文獻仍相當缺乏。在本博士論文的第一部份研究中，我們針對不同大小(較小粒徑 v.s.較大粒徑)與不同表面修飾(檸檬酸v.s.半胱胺)之奈米銀(總共四種，包括SCS, LCS, SAS與LAS)所誘發之毒性機轉，透過體外試驗、電腦模擬及體內試驗等方法，來進行現象上的觀察與機轉上的探討。為了符合減量，取代與優化的三原則，我們採取結合了決策樹理論與資料庫知識探索程序之電腦模擬方法來排比會影響奈米毒性之相關參數：暴露劑量、暴露時間、細胞株的選擇、與奈米銀的類型。根據所建立之預測模型，這四個參數對奈米銀誘發細胞毒性的影響排序如下：暴露時間>細胞株的選擇>奈米銀種類≥暴露時間。藉由預測模型所獲得之知識讓我們將這部分的研究從細胞層級上的現象觀察轉型成更精深的體外與體內機轉研究。不論奈米銀的種類為何，只要是能造成顯著細胞毒性的劑量，奈米銀就會透過引發細胞凋亡(非引發細胞壞死)來降低細胞的存活率，同時也會在暴露的初期活化自噬作用，這可視為一種能保護細胞降低奈米銀毒性影響的早期事件。此外，長時間暴露在不會影響細胞存活的劑量下，奈米銀可能會讓細胞進入G2/M細胞休止期，而後走向細胞老化。非常有趣的一件事是，我們發現表面帶負電的SCS微粒，跟表面帶正電的SAS微粒相比，經由腹腔注射到體內，會對BALB/c小鼠產生更強烈的毒性。不過這兩種奈米銀微粒注入腹腔後，都會沈積在許多器官(例如：脾臟、肝臟與腎臟)。除了會引發肝臟發炎之外，根據直接的外觀觀察、血清化學以及組織病理檢測的結果，我們發現致死劑量的奈米銀急性暴露還會對胰臟造成破壞，並且讓血糖濃度上升。

在此博士論文的第二部分研究中，我們使用了一種強大的替代性體內測試平台-果蠅模式-來探討攝入的奈米銀在個體、細胞以及分子的層級上，所引發的各種危害效應。攝入致死劑量的奈米銀會讓果蠅的幼蟲發育遲緩，並且提高受暴露的幼蟲及剛羽化的成蟲的死亡率。很重要的一點是，暴露亞致死劑量，即使對發育中的幼蟲不會產生顯著的危害，仍然會讓羽化後的成蟲的壽命縮短，並且也會顯著降低它們對氧化壓力的耐受力。攝入致死劑量的奈米銀會造成系統性的自由基累積，透過Nrf2報導系統轉殖的果蠅進行研究，顯示奈米銀的暴露會啟動Nrf2抗氧化途徑，此外也會誘發許多藉由自由基來做介導的壓力反應，包括細胞凋亡、DNA損傷、與自噬作用。此外，奈米銀的暴露也會削弱幼蟲蠕動與成蟲攀爬的能力，而這可能歸因於我們所觀察到奈米銀對粒線體的結構與功能上的負影響。在分子層級，我們發現增強對粒線體內平衡維持很重要的伴護蛋白TRAP1之表達可以顯著提升果蠅對奈米銀的抗性，降低它們的死亡率與改善它們的運動能力。

總的來說，這個結合了體外試驗、電腦模擬與果蠅模式實驗的研究成果，可讓我們對奈米銀誘發之系統性與器官專一性毒性的機轉，同時在細胞、亞細胞與分子層次上獲得更深入的見解。此外，根據我們的研究成果，我們提出呼籲要小心長期暴露在亞致死或環境相關低劑量下奈米銀對人類的壽命與健康狀態也可能會產生危害效應。

The exponential growth in nanotechnology industry has guaranteed matching progress in the nanotoxicology and risk assessment fields. Mammalian models have been extensively used to determine human and environmental risks arising from exposure to chemicals; however, the use of these in vivo platforms in research has been subject to condemnation, owing to ethical considerations for several decades. Global appeals are being launched for developing reliable alternatives to mammalian organisms-based testing approaches. Although various alternative testing strategies (ATS) (e.g., in vitro and in silico approaches, and usage of non-mammalian models) have been rapidly established, distinctive physico-chemical features of engineered nanoparticles (ENPs) bring forth distinct considerations from traditional chemicals, display-ing new requirements for modifying these testing approaches for ENPs.

Silver nanoparticles (AgNPs) are considered a double-edged sword that demonstrates advantageous and unfavorable effects depending on their physico-chemical characteristics, especially dimensions and surface coating types. However, mechanistic reports regarding size- and coating agent-dependent adverse effects of AgNPs remain inadequate in vitro and in vivo. In the first part of this dissertation, we phenotypically and mechanistically explore the toxicity mechanisms of AgNPs with distinct sizes (i.e., smaller v.s. larger) and dissimilar surface coatings (i.e., citrate v.s. cysteamine) (totally four AgNP types: SCS, LCS, SAS, and LAS) through integration of in vitro, in silico, and in vivo approaches. In keeping with the 3R principles, a decision tree-based knowledge-discovery-in-databases (KDD) process was adopted to rank the toxicity-relevant attributes, including dose, time, choice of cell type, and particle type. As predicted by the tree model, the order of influence towards AgNPs-induced cytotoxicity was as follows. dose > cell type > particle type ≥ time. The acquired knowledge was employed to transform this research form cell-based phenomenological observations to further in vitro and in vivo mechanistic explorations. Regardless of particle type, AgNPs at cytotoxic doses triggered apoptosis rather than necrosis to compromise cell viability; in the meanwhile, the exposure could also activate autophagy, which might serve as an early cyto-protective event against AgNPs-induced damage. Chronic exposure to non-cytotoxic doses of AgNPs might allow the cells to undergo G2/M cell cycle arrest and render them senescent. Intriguingly, negatively charged SCS, via intraperitoneal (IP) injection, appeared more toxic to BALB/c mice than positively charged SAS. Both AgNP types could be found deposited in various organs (e.g., spleen, liver, and kidneys). Apart from leading to hepatic inflam-mation, direct morphological examination, accompanied by serum biochemistry and histo-logical analysis, indicated that lethal-dose AgNPs exposure could incur severe damage to pancreas and raise blood glucose levels at the early phase of exposure.

In the second part of this dissertation, we used a powerful alternative in vivo platform, Drosophila melanogaster, to explore a wide-spectrum of adverse effects exerted by dietary AgNPs at the organismal, cellular and molecular levels. Lethal doses of dietary AgNPs led to developmental delay and profound lethality of the larvae and young adults. Importantly, exposure to sublethal doses, while not deleterious to developing animals, shor-tened the adult lifespan and compromised their tolerance towards oxidative stress. Under the lethal scenario, dietary AgNPs mechanistically led to systemic accrual of reactive oxygen species (ROS); they correspondingly activated the Nrf2-dependent antioxidant pathway, as revealed by an in vivo Nrf2 activity reporter. Our research data suggested that dietary AgNPs caused a variety of ROS-mediated stress responses, including apoptosis, DNA damage, and auto-phagy. In addition, such exposure also impaired crawling and climbing performance of the larval and adult flies, respectively, which might be attributable to AgNPs negative impacts on mitochondrial structure and function. At the molecular level, we identified that over-expression of TRAP1, a chaperone protein crucial for mitochondrial homeostasis, signifi-cantly conferred resistance to AgNPs toxicity upon flies, by reducing mortality and improv-ing motor performance.

In conclusion, the findings from this integrative in vitro, in silico, and Drosophila-based research could shed light on the cellular, subcellular and molecular mechanisms of AgNPs systemic and organ-specific toxicity. Besides, our data also put forward the caution for the adverse impacts of long-term exposure to sublethal, or even environmentally-relevant low concentrations of AgNPs on human life-span and healthspan.

博士論文口試合格證明……………………………………………………………………………I
Abstract in Chinese………………………………………………………………………………II
Abstract in English………………………………………………………………………………IV
致謝…………………………………………………………………………………………………VI
Abbreviation……………………………………………………………………………………XVI
Publication list…………………………………………………………………………………XVIII
Introduction………………………………………………………………………………………1
1.	The imperious demands for interrogating the mechanisms of AgNPs-induced toxicity………………………………………………………………………………………………1 
2.	The important parameters dictating toxicity and biocompatibility of AgNPs………………………………………………………………………………………………3
3.	Integrative alternative testing strategies for nanotoxicological research……………………………………………………………………………………………5
4.	Drosophila as powerful model for assessing the mechanisms of nanotoxicity………………………………………………………………………………………7
Objectives…………………………………………………………………………………………9
Materials and Methods………………………………………………………………………10
1.	Fabrication and characterization of SCS, LCS, SAS and LAS particles…………10
2.	Preparation of smaller-sized RBITC-conjugated AgNP particles…………………11
3.	Cell lines and culture conditions………………………………………………………11
4.	In vitro AgNPs exposure…………………………………………………………………12
5.	Cell viability assessment…………………………………………………………………12
6.	Decision tree-based KDD process……………………………………………………13
7.	Apoptosis assay by flow cytometry……………………………………………………13
8.	Autophagy assay by flow cytometry…………………………………………………14
9.	Cell cycle analysis…………………………………………………………………………14
10.	Senescence-associated -galactosidase activity assay…………………………14
11.	Clonogenic assay…………………………………………………………………………15
12.	Western blot analysis……………………………………………………………………15
13.	In vivo exposure……………………………………………………………………………15
14.	Serum biochemistry analysis……………………………………………………………16
15.	Biodistribution and bioaccumulation assessments…………………………………16
16.	Macroscopic and histopathological examinations………………………………17
17.	Drosophila strains…………………………………………………………………………17
18.	Dietary AgNPs exposure………………………………………………………………… 17 
19.	Atomic absorption spectrometry………………………………………………………18
20.	Longevity assay……………………………………………………………………………18
21.	Paraquat challenge assay………………………………………………………………18
22.	Dihydroethidium (DHE) staining…………………………………………………………19
23.	ARE reporter gene induction assay……………………………………………………19
24.	Whole-mount immunofluorescence analyses of apoptosis and DNA damage…………………………………………………………………………………………19
25.	ATP luminescence assay……………………………………………………………… 19
26.	Climbing assay……………………………………………………………………………20
27.	Crawling assay……………………………………………………………………………20
28.	mtDNA copy number assay……………………………………………………………20
29.	Statistical analysis…………………………………………………………………………21
Experimental design………………………………………………………………………… 22
Part 1: Use of an in silico knowledge discovery approach to translate mechanistic studies of silver nanoparticles-induced toxicity from in vitro to in vivo………………22
Part 2: Use of Drosophila melanogaster as a non-mammalian alternative model 
system to explore the mechanisms of systemic toxic effects exerted by ingested 
silver nanoparticles at the cellular, subcellular and molecular levels………………22
Results…………………………………………………………………………………………… 23
Part 1: Use of an in silico knowledge discovery approach to translate mechanistic 
studies of silver nanoparticles-induced toxicity from in vitro to in vivo………………23
1.1.	Physicochemical properties of SCS, LCS, SAS, and LAS……………………………23
1.2.	Exposures to SCS, LCS, SAS and LAS induced cytotoxicity in both dose-dependent and cell type-specific manners………………………………………………24
1.3.	Predictive modeling of AgNPs-evoked toxicity through the decision tree-based KDD process……………………………………………………………………………………………26
1.4.	Apoptosis as an underlying mechanism of AgNPs-induced cell demise………28
1.5.	Autophagy as an early cytoprotective event against AgNPs-induced toxicity……………………………………………………………………………………………29
1.6.	AgNPs at non-cytotoxic doses had the potential to cause G2/M cell cycle arrest and senescence………………………………………………………………………30
1.7.	AgNPs exposure differentially triggered apoptosis, autophagy and cell cycle arrest in a dose-dependent fashion………………………………………………………31
1.8.	Exposure to AgNPs via intraperitoneal (IP) injection caused acute toxicity in mice and displayed differential organ distribution and accumulation……………34
1.9.	Acute exposure to toxic/lethal doses of AgNPs caused profound pancreatic injury……………………………………………………………………………………………….36
Part 2: Use of Drosophila melanogaster as a non-mammalian alternative model 
system to explore the mechanisms of systemic toxic effects exerted by ingested 
silver nanoparticles at the cellular, subcellular and molecular levels………………37
2.1.  Silver nanoparticles cause lethal and sublethal adverse effects on development and longevity of Drosophila melanogaster by inducing ROS-mediated stress responses……………………………………………………………………37
2.1.1. Physicochemical characterization of synthetic citrate-capped AgNPs……37
       2.1.2. Lethal doses of AgNPs exposure increased larval mortality and interfered 
with larval development………………………………………………………………………38
       2.1.3. Lethal-dose AgNP exposure prolonged the duration of the pupal stage and reduced the eclosion success…………………………………………………………38
       2.1.4. Silver deposition within adult flies having received exposure to AgNPs 
during the larval stage…………………………………………………………………………39
       2.1.5. Sublethal AgNPs exposure shortened the adult lifespan and compromised the stress tolerance capacity………………………………………………………………39
       2.1.6. Lethal AgNPs exposure resulted in generation of ROS and activation of the Nrf2-dependent antioxidant response………………………………………………40
       2.1.7. Lethal AgNPs exposure induced apoptosis and led to double-strand DNA 
breaks…………………………………………………………………………………………… 41
       2.1.8. Lethal AgNPs exposure contributed to profound activation of autophagy………………………………………………………………………………………41
2.2.  Other aspects concerning AgNPs-induced adverse effects in vivo……………42
       2.2.1. AgNPs compromised locomotor ability of the exposed flies……………… 42
       2.2.2. Ingested AgNPs seemed to evoke structural and functional impairments of mitochondria in vivo ………………………………………………………………………42
    2.3.  Exploring the molecular fundamentals of AgNPs-induced mitotoxicity using the Drosophila model - TRAP1 as an example (unpublished data)…………………43
       2.3.1. The expression level of TRAP1 could dictate the susceptibility of Drosophila 
to AgNPs-induced toxicity……………………………………………………………………44
Discussion…………………………………………………………………………………………45
1.	Part 1. Use of an in silico knowledge discovery approach to translate mechanistic studies of silver nanoparticles-induced toxicity from in vitro to in vivo……………………………………………………………………………………………… 45
2.	Part 2: Use of Drosophila melanogaster as a non-mammalian alternative model system to explore the mechanisms of systemic toxic effects exerted by ingested silver nanoparticles at the cellular, subcellular and molecular levels……………….49
3.	Future perspective……………………………………………………………………… 54
Conclusion………………………………………………………………………………………55
Declaration of contributions to this dissertation research………………………………56
References………………………………………………………………………………………57
Tables and Figures…………………………………………………………………………….71
Appendix………………………………………………………………………………………109
                                    

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