臺灣博碩士論文加值系統

近年來不斷爆發食安問題，飲食中的食品汙染物可能會引起人類疾病及癌症的產生，精製食用油加工過程會產生高含量的食品汙染物單氯丙二醇(3-MCPD)及縮水甘油(Glycidol)。動物實驗結果證實，長期攝取高劑量3-MCPD及Glycidol可能會造成腎臟損傷。而細胞實驗發現，3-MCPD及Glycidol引起的腎毒性可能是經由損傷粒腺體氧化磷酸化系統，並誘導細胞凋亡造成細胞傷害，且最近研究發現越來越多新的細胞死亡類型與粒腺體損傷有關。因此，本研究的目的為探討單獨或合併處理3-MCPD及Glycidol是否會經由粒腺體功能受損及活化NLRP3發炎體、pyroptosis、自噬作用、necroptosis及ferroptosis等多種細胞死亡模式來造成腎臟損傷。3-MCPD及Glycidol已被證實同時存在於汙染的食品中，而共同暴露是否具有協同作用且毒性機轉仍不清楚。因此，我們利用動物、細胞實驗以及次世代基因體定序分析，以了解3-MCPD、Glycidol單獨或共同暴露下造成腎臟損傷之分子機轉，並評估紫檀芪預防3-MCPD及Glycidol造成腎臟損傷之效果及機制。
本研究使用C57BL/6小鼠單獨或合併管餵28天的3-MCPD (10、25、50、75及100 mg/kg)、Glycidol(10、25、50、100及150 mg/kg)或紫檀芪(200mg/kg)，採取其腎臟組織進行H＆E染色及免疫組織化學染色以觀察腎臟毒性及紫檀芪預防效果，且利用腎臟組織進行次世代基因體定序分析，以了解3-MCPD或Glycidol單獨或共同暴露並合併紫檀芪下造成腎臟損傷及天然物預防之分子機轉。在細胞實驗中，使用大鼠腎小管上皮細胞(NRK-52E)單獨或合併處理3-MCPD、Glycidol或紫檀芪。利用MTT分析細胞存活率，以流式細胞儀觀察粒腺體損傷及細胞死亡現象，並使用乳酸脫氫酶分析套組及西方墨點法來檢測發炎體活化、pyroptosis、necroptosis、ferroptosis及自噬作用相關機制。
在動物實驗中，高劑量3-MCPD(M75和M100)或合併Glycidol(M+G)的組別中，具有體重下降及相對腎臟重量上升的情形。組織病理學結果發現，經由3-MCPD及Glycidol處理的腎臟組織具有腎小管變性、擴張及壞死等現象，次世代定序結果中發現共同暴露組別影響發炎及細胞週期相關路徑且在組織免疫化學染色法會誘導自噬作用的產生。在預防策略的動物模式中，給予天然物紫檀芪可有效緩解3-MCPD及Glycidol所造成的腎毒性。在生化分析及組織病理學的結果中可以看到，處理低劑量的3-MCPD或Glycidol結合紫檀芪可有效地降低血清及尿液中的腎臟指標且並未觀察到腎小管擴張及變性等情形。
在體外試驗中，NRK-52E細胞處理3-MCPD或Glycidol後，其存活率顯著下降並具有劑量效應關係。給予細胞3-MCPD或Glycidol造成粒腺體膜電位下降且在處理 24、48及72小時後，可觀察到NLRP3發炎體、pyroptosis、necroptosis、ferroptosis及細胞自噬相關蛋白的表現量上升，證實3-MCPD或Glycidol所造成的腎臟損傷是由粒腺體受損及多種細胞死亡共同調節的。為了模擬3-MCPD及Glycidol同時存在於汙染的食品中，將細胞共同暴露於3-MCPD和Glycidol進行協同效應的分析，且透過西方墨點法及免疫螢光染色探討共同暴露會誘導自體吞噬及necroptosis的細胞死亡模式來造成腎毒性。綜合上述實驗結果，本研究證實3-MCPD及Glycidol單獨或共同暴露造成腎臟損傷與粒腺體功能受損及多種細胞死亡共同調節有關，而在預防策略中，天然物紫檀芪可以有效減緩3-MCPD及Glycidol的腎毒性。

Refined edible oil produces high amounts of food contaminants such as 3-monochloropropanediol (3-MCPD) and Glycidol during processing. Previous animal studies have demonstrated the renal damage could be induced by chronic ingestion with high doses of 3-MCPD and Glycidol. The mechanistical studies have shown that nephrotoxicity induced by 3-MCPD and Glycidol is partially through damage the oxidative phosphorylation system of mitochondria leading to induced apoptosis cell death. An increasing number of cell death types has been discovered in response to mitochondria damage. Thus, we aim to study the cell death mechanisms of renal damage after 3-MCPD and Glycidol treatment alone or in combination in vitro and in vivo. Through the established animal, cell models and the NGS results in our study, we can provide the renal toxicity evidences of 3-MCPD combined with Glycidol and the natural compound pterostilbene for studying the preventive targets for renal diseases. In the in vivo study, we demonstrate that 3-MCPD and Glycidol significantly induce the renal toxicity in C57BL/6 mice. Interestingly, the co-exposure of 3-MCPD and Glycidol significantly induced synergistic toxic effects of renal in animal models. In the preventive model, pterostilbene (PT) could significantly alleviated renal toxicity induced by 3-MCPD or Glycidol. We suggest that PT could be an effective agent for reducing renal toxicity induced by food contaminants. In the in vitro study, we indicate that 3-MCPD and Glycidol significantly induced cytotoxicity in NRK-52E cells. 3-MCPD and Glycidol treatment induced NLRP3 inflammasome, pyroptosis, necroptosis and ferroptosis in renal cells. The synergistic toxic effects of 3-MCPD and Glycidol showed significantly increased in autophagic cell death. In conclusion, we suggest the molecular mechanisms of renal toxicity caused by 3-MCPD and Glycidol treatment alone or in combination via mitochondrial damage and induction of pyroptosis, ferroptosis, necroptosis and autophagy.

中文摘要 I
英文摘要 III
第一章、序論 1
第二章、文獻回顧 2
第一節、食品汙染物單氯丙二醇(3-MCPD)及縮水甘油(Glycidol) 2
第二節、透過次世代定序分析釐清複雜之腎臟損傷機制 6
第三節、粒腺體及NLRP3發炎體活化 8
第四節、 程序性細胞死亡 (Programmed cell death) 10
(一) 細胞凋亡 (Apoptosis) 10
(二) 自噬作用 (Autophagy) 11
(三) 發炎性細胞凋亡 (Pyroptosis) 12
(四) 鐵依賴性細胞凋亡 (Ferroptosis) 13
(五) 壞死性細胞凋亡 (Necroptosis) 14
第五節、 紫檀芪 (Pterostillbene) 16
第三章、研究目的 17
第四章、研究材料與方法 18
第一節 研究材料 18
(一) 細胞株： 18
(二) 儀器： 18
(三) 試劑與耗材: 19
第二節 研究方法與實驗步驟 22
(一) 動物實驗： 22
1. 動物飼育管理 22
2. 動物馴化及檢疫 22
3. 【毒性試驗動物模式】 23
4. 【預防策略動物模式】 23
5. 血球分析 23
6. 生化值分析 23
7. Creatinine和BUN清除率計算 24
8. 尿酸分析 24
9. 尿液KIM-1分析 24
10. 蘇木紫伊紅染色(Hematoxylin ＆ Eosin Staining) 24
11. 纖維化染色法Masson’s Trichrome Stain 25
12. 免疫組織化學染色法(immunohistochemistry, IHC) 25
13. 次世代定序分析 26
(二) 細胞實驗： 26
1. 細胞解凍 27
2. 細胞冷凍 27
3. 細胞培養(Cell culture) 27
4. 細胞存活率(Cell viability) 28
5. 協同效應分析 (Synergistic interaction) 28
6. 粒腺體膜電位 (Mitochondria membrane potential, MMP)分析 28
7. LDH assay 28
8. 細胞凋亡分析(Apoptosis assay) 28
9. 自噬作用分析(Autophagy assay) 29
10. 免疫螢光染色(Immunofluorescence) 29
11. 西方墨點法(Western blot) 30
12. 統計分析 31
第五章、研究架構 32
第六章、實驗結果 35
第一節、食品汙染物3-MCPD及Glycidol單獨或共同暴露之毒性試驗動物模式 35
第二節、食品汙染物3-MCPD及Glycidol誘導C57BL/6小鼠腎臟損傷 36
第三節、利用次世代基因分析，釐清複雜之腎臟損傷機制 38
第四節、大鼠腎小管上皮細胞NRK-52E Cells暴露於食品汙染物3-MCPD及Glycidol所誘導的細胞毒殺效應並分析協同作用 39
第五節、食品汙染物3-MCPD及Glycidol造成NRK-52E細胞粒腺體功能受損、NLRP3發炎體活化及發炎性細胞凋亡 (Pyroptosis) 40
第六節、食品汙染物3-MCPD及Glycidol造成NRK-52E細胞誘導鐵依賴性細胞死亡 (Ferroptosis) 42
第七節、食品汙染物3-MCPD及Glycidol造成NRK-52E細胞誘導壞死性細胞凋亡(Necroptosis) 43
第八節、食品汙染物3-MCPD及Glycidol造成NRK-52E細胞引起自噬 (Autophagy) 作用的細胞死亡 44
第九節、天然物紫檀芪 (Pterostillbene) 合併食品汙染物3-MCPD及Glycidol減緩腎毒性之預防策略動物模式 46
第七章、討論 48
第八章、結論及建議 57
第九章、參考文獻 59

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