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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉秉慧 | zh_TW |
| dc.contributor.advisor | Biing-Hui Liu | en |
| dc.contributor.author | 劉明源 | zh_TW |
| dc.contributor.author | Ming-Yuan Liu | en |
| dc.date.accessioned | 2026-03-13T16:47:00Z | - |
| dc.date.available | 2026-03-14 | - |
| dc.date.copyright | 2026-03-13 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-11-18 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/102144 | - |
| dc.description.abstract | 白僵菌素 (Beauvericin, BEA) 與恩鏈黴素B (Enniatin B, ENNB) 為鐮孢菌屬 (Fusarium) 真菌所產生的新興黴菌毒素，常污染飼料與穀物等食品原料，其對人類與動物健康的潛在威脅日益受到重視。由於白僵菌素與恩鏈黴素B 皆具陽離子載體 (Ionophore) 特性，本研究假設心臟可能為其主要毒性靶器官，並以心臟毒性作為探討重點。在體內模式中，1–4 μM 白僵菌素可明顯促進野生型斑馬魚胚胎之心跳速率與血液輸出量，反映白僵菌素對心臟收縮功能及血液動力學具有急性促進效應。白僵菌素亦造成心臟螢光 Tg(BMP4:EGFP)as1 斑馬魚胚胎靜脈竇至動脈球的直線距離顯著增加，呈現白僵菌素會造成心臟折疊結構異常；但恩鏈黴素B 處理斑馬魚胚胎則未觀察到心率與心臟折疊結構的顯著變化。在體外模型方面，使用大鼠 H9c2 心肌母細胞株探討白僵菌素的心臟毒性機制。使用 MTT 分析細胞存活率，呈現出 H9c2 細胞株暴露於 1–4 μM 白僵菌素達 72 小時後，其存活率與相同濃度之 24 小時相比並無顯著差異；此外，經流式細胞儀分析顯示，白僵菌素使細胞週期顯著停滯於 G1 期。轉錄體學分析與 RT-qPCR 驗證結果指出，白僵菌素處理後在 DNA 複製相關基因 (Cdc6、Mcm2–7) 表達量顯著下降。進一步以 PCNA 蛋白質表達量及 EdU/BrdU 核苷相似物分析 DNA 複製能力，發現白僵菌素長時間處理可顯著抑制 H9c2 細胞株的 DNA 複製活性。在細胞增生評估中，分析 48 小時即時影像觀察、pHH3 (Ser10) 蛋白質表達與有絲分裂指數等指標，結果顯示 2–4 μM 白僵菌素可顯著抑制 H9c2 細胞株之細胞增生；同時，在 DNA 損傷指標方面，白僵菌素處理後微核數目與 DNA 斷裂現象顯著上升。在分子層次上，以 4 μM 白僵菌素短時間 (1 小時) 處理 H9c2 細胞株顯著抑制 DNA 複製相關蛋白質表達量 (CDC6, MCM2 與 PCNA)；此外，在 DNA 修復與損傷蛋白質表達方面，白僵菌素處理後並未顯著改變 pRPA (Ser33) 蛋白質表達量，但卻造成 pCHK1 (Ser345) 與 γH2AX (Ser139) 的表達量顯著提升，顯示白僵菌素的短時間處理可能會抑制 DNA 複製並造成 DNA 損傷與修復機轉活化；將細胞週期同步於 G1 後期，暴露於 4 μM 白僵菌素 3 小時，再將毒素移除 1 小時與 3 小時後，結果發現 PCNA 蛋白質與 γH2AX (Ser139) 蛋白質表達量呈高度正相關；再利用 BrdU 標定的 DNA 複製區域與 γH2AX (Ser139) DNA 損傷指標在細胞核內高度重疊，顯示白僵菌素會誘導 DNA 複製與損傷事件相伴而生之現象。綜合以上結果，本研究證實白僵菌素處理斑馬魚胚胎令其產生心臟毒性，並可誘發大鼠 H9c2 心肌母細胞株中 DNA 複製壓力及相關 DNA 損傷現象，為白僵菌素毒性機制提供初步分子層級證據。 | zh_TW |
| dc.description.abstract | Beauvericin (BEA) and Enniatin B (ENNB) are emerging mycotoxins produced by Fusarium species, commonly contaminating feed and grain-based food products; thus, their potential threat to human and animal health has received increasing attention. Based on the ionophore property of BEA and ENNB, this study hypothesized that the heart may serve as a primary target organ for their toxicity. In the in vivo model, exposure to 1–4 μM BEA significantly increased heart rate and cardiac output in wild-type zebrafish embryos, indicating an acute stimulatory effect on cardiac contractility and hemodynamics. BEA treatment also caused a marked increase in the linear distance between the sinus venosus and the bulbus arteriosus in Tg(BMP4:EGFP)as1 cardiac fluorescent zebrafish embryos, reflecting impaired cardiac looping. In contrast, ENNB exposure did not induce significant changes in heart rate or cardiac folding structure. In the in vitro model, the rat cardiomyoblast cell line H9c2 was used to investigate the cardiotoxic mechanisms of BEA. According to the MTT assay, exposure of H9c2 cells to 1–4 μM BEA for 72 hours did not result in a significant difference in cell viability compared with the same concentrations at 24 hours. Flow cytometry analysis indicated that BEA induced a significant G1 phase arrest. Transcriptomic analysis and RT-qPCR validation further showed a significant downregulation of DNA replication–related genes, including Cdc6 and Mcm2–7. Consistently, PCNA protein expression and EdU/BrdU incorporation assays demonstrated that BEA markedly suppressed DNA replication activity in H9c2 cells. Cell proliferation analysis—including 48-hour time-lapse imaging, pHH3 (Ser10) protein detection, and mitotic index quantification—revealed that 2–4 μM BEA significantly inhibited cell proliferation. Meanwhile, micronucleus formation and comet assay results indicated increased DNA damage upon BEA exposure. At the molecular level, short-term treatment (1 hour) of H9c2 cells with 4 μM BEA significantly suppressed the expression of DNA replication-related proteins (CDC6, MCM2, and PCNA). In contrast, the expression levels of pCHK1 (Ser345) and γH2AX (Ser139) were markedly increased, whereas pRPA (Ser33) remained unchanged, suggesting that BEA rapidly induces DNA damage and activates DNA damage response pathways. Furthermore, when cells were synchronized in late G1 and exposed to 4 μM BEA for 3 hours, followed by toxin removal for 1 and 3 hours, PCNA expression showed a strong positive correlation with γH2AX (Ser139) levels. Fluorescent co-localization analysis further confirmed that BrdU-labeled replication signals and γH2AX (Ser139) DNA damage foci extensively overlapped in nuclei, indicating that DNA replication and damage events are coupled. Taken together, the present study demonstrates that BEA treatment induces cardiotoxicity in zebrafish embryos and triggers replication stress–associated DNA damage in rat H9c2 cardiomyoblasts. These findings provide preliminary molecular-level evidence for the underlying mechanisms of BEA toxicity. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2026-03-13T16:47:00Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2026-03-13T16:47:00Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 論文口試委員審定書 i
誌謝 ii 中文摘要 (Chinese Abstract) iii 英文摘要 (English Abstract) v 圖形摘要 (Graphic Abstract) vii 目次 viii 圖次 xi 第一章 緒論 (Introduction) 1 1.1白僵菌素與恩鏈黴素B 背景介紹 1 1.2白僵菌素與恩鏈黴素B 的汙染量 3 1.3白僵菌素與恩鏈黴素B 具有陽離子載體的特性 4 1.4白僵菌素與恩鏈黴素B 的神經毒性 5 1.5白僵菌素與恩鏈黴素B 的腎臟毒性 6 1.6白僵菌素與恩鏈黴素B 的肝臟毒性 7 1.7白僵菌素的心臟毒性 7 1.8白僵菌素的 DNA 損傷現象 8 1.9白僵菌素的抑癌能力 9 1.10 DNA 複製起始 10 1.11 DNA 複製延長 11 1.12 DNA 複製壓力 (DNA replication stress) 12 1.13 DNA 複製壓力損傷修復機制 12 1.14斑馬魚胚胎動物模型 14 1.15 H9c2 心肌母細胞株模型 15 研究動機與目的 17 第二章 材料與方法 (Materials and Methods) 18 2.1實驗材料 18 2.1.1藥品 18 2.1.2試劑 19 2.1.3細胞培養材料 20 2.1.4斑馬魚 20 2.1.5細胞株 20 2.1.6抗體 21 2.1.7儀器設備 22 2.1.8定量聚合酶鏈鎖反應之引子 22 2.2實驗方法 22 2.2.1斑馬魚飼育 22 2.2.2斑馬魚胚胎之黴菌毒素處理 23 2.2.3斑馬魚胚胎心臟螢光影像 23 2.2.4斑馬魚胚胎心臟之功能分析 24 2.2.5細胞培養、繼代與計數 25 2.2.6細胞凍存 26 2.2.7細胞之黴菌毒素處理 26 2.2.8細胞存活率分析 (MTT assay) 27 2.2.9細胞斷層掃描分析 (Nanolive image) 28 2.2.10細胞週期分析 (Cell cycle analysis) 28 2.2.11細胞週期同步化 29 2.2.12 RNA萃取 30 2.2.13次世代定序與轉錄體學的生物資訊學分析 30 2.2.14反轉錄-及時定量聚合酶鏈鎖反應 32 2.2.15細胞全蛋白質萃取 33 2.2.16西方墨點法 33 2.2.17免疫螢光 34 2.2.18 EdU 細胞增生分析 (EdU assay) 35 2.2.19 BrdU 標定細胞複製分析法 (BrdU labeling) 36 2.2.20細胞有絲分裂指數法 (Mitotic index) 37 2.2.21微核分析法 (Micronucleus assay) 38 2.2.22鹼性彗星分析法 (Alkaline comet assay) 39 2.2.23 BrdU 與 γH2AX (Ser139) 之共定位螢光與分析法 40 2.2.24統計分析 40 第三章 結果 (Results) 42 3.1白僵菌素對斑馬魚胚胎外型的效應 42 3.2白僵菌素具有干擾斑馬魚心臟功能的特性 42 3.3恩鏈黴素B 對斑馬魚胚胎之影響 43 3.4白僵菌素抑制 H9c2 細胞株的增生能力 44 3.5白僵菌素對 H9c2 細胞株之細胞週期影響 44 3.6白僵菌素對 H9c2 細胞株轉錄體的分析 45 3.7白僵菌素對 H9c2 細胞株在 DNA 複製複合體基因效應 46 3.8白僵菌素抑制 H9c2 細胞株複製 DNA 的能力 46 3.9白僵菌素抑制 H9c2 細胞株的細胞分裂和增生 47 3.10白僵菌素顯著促進 H9c2 細胞株的微核生成和 DNA 斷裂 48 3.11白僵菌素在短時間內抑制 H9c2 細胞株 DNA 複製相關蛋白質的表達量 49 3.12白僵菌素對於 DNA 複製壓力相關之 DNA 損傷修復訊號影響 50 3.13白僵菌素處理令 DNA 複製及 DNA 損傷蛋白質之表達趨勢及位點一致 51 第四章 討論 (Discussion) 52 第五章 結論 (Conclusion) 64 第六章 參考文獻 (References) 89 附錄 (Appendices) 113 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 白僵菌素 | - |
| dc.subject | 斑馬魚胚胎 | - |
| dc.subject | H9c2 心肌母細胞株 | - |
| dc.subject | 心臟毒性 | - |
| dc.subject | DNA 複製壓力 | - |
| dc.subject | DNA 損傷 | - |
| dc.subject | Beauvericin | - |
| dc.subject | Zebrafish embryos | - |
| dc.subject | H9c2 cardiomyoblasts | - |
| dc.subject | Cardiotoxicity | - |
| dc.subject | DNA replication stress | - |
| dc.subject | DNA damage | - |
| dc.title | 探討白僵菌素之心臟毒性及DNA複製壓力所扮演的角色 | zh_TW |
| dc.title | Studying the Cardiotoxicity of Beauvericin and its Role in DNA Replication Stress | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 114-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 傅淑玲;黃晟洋 | zh_TW |
| dc.contributor.oralexamcommittee | Shu-Ling Fu;Cheng-Yang Huang | en |
| dc.subject.keyword | 白僵菌素,斑馬魚胚胎H9c2 心肌母細胞株心臟毒性DNA 複製壓力DNA 損傷 | zh_TW |
| dc.subject.keyword | Beauvericin,Zebrafish embryosH9c2 cardiomyoblastsCardiotoxicityDNA replication stressDNA damage | en |
| dc.relation.page | 141 | - |
| dc.identifier.doi | 10.6342/NTU202504671 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-11-19 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 毒理學研究所 | - |
| dc.date.embargo-lift | 2026-03-14 | - |
| 顯示於系所單位： | 毒理學研究所 | |
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