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研究生： 朱鈞薇
Chu, Chun-Wei
論文名稱： 聚苯乙烯塑膠微粒透過粒線體損傷進而誘導肝臟脂質代謝及能量紊亂
Polystyrene microplastics induce hepatic lipid metabolism and energy disorder by mitochondrial damage
指導教授： 李宥萱
Lee, Yu-Hsuan
學位類別： 碩士
Master
系所名稱： 醫學院 - 食品安全衛生暨風險管理研究所
Department of Food Safety / Hygiene and Risk Management
論文出版年： 2020
畢業學年度： 108
語文別： 中文
論文頁數： 90
中文關鍵詞： 塑膠微粒 、能量代謝 、粒線體損傷 、AMP-活化蛋白激酶（AMPK） 、自噬作用 、外泌體
外文關鍵詞： Microplastics, Energy metabolism, Mitochondria damage, AMPK, Autophagy, Exosome
相關次數： 點閱：70  下載：1 
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    • 近年來，直徑< 5 mm的塑膠顆粒被認為會對全球環境和人類健康危害帶來風險。人類可以直接從環境或通過食物暴露到塑膠微粒（MPs）。有研究證明，MPs暴露可能導致能量和脂質代謝的破壞、誘導氧化壓力並產生神經毒性反應。然而，對於其毒性機制仍舊不清楚。肝臟是最大的代謝器官之一，在能量代謝中扮演重要的角色。本研究的目的是探討聚苯乙烯塑膠微粒（PS-MPs）是否影響粒線體的功能並且促進AMP-活化蛋白激酶（AMPK）路徑的活化，調控autophagy路徑及脂質代謝進行討論，此外進一步評估塑膠微粒是否會影響外泌體的分泌。
    本研究使用螢光與非螢光且尺寸為2 μm及100 nm之PS-MPs。在動物實驗中，C57BL / 6公鼠管餵螢光PS-MPs以觀察其在體內的分佈。無螢光PS-MPs進行毒性試驗暴露四週及八週後犧牲。在體外實驗中，利用正常小鼠肝細胞（AML-12）進行實驗，以Dioc6及MitoSOX觀察粒線體的損傷情形，並以real-time PCR和Western blotting來分析相關miRNA和蛋白表現量。外泌體的分離是收集AML-12細胞的上清培養液經由差異離心取得，並使用穿透式電子顯微鏡（TEM）、奈米粒子追蹤分析（NTA）及流式細胞儀分析外泌體的特徵與含量。
    螢光PS-MPs暴露後於動物體內的分布情形顯示，PS-MPs可能經由肝臟代謝而累積或儲存在肝臟。在毒性試驗動物模式中給予PS-MPs的組別會使肝組織TG及血清生化值TG和T-CHO下降且在肝臟組織切片中也發現有小脂滴的存在。小鼠暴露2 μm PS-MPs及100 nmPS-MPs皆會促進p-AMPK-α蛋白表現，由動物及細胞實驗結果證實2 μm PS-MPs相較於100 nm PS-MPs引起的肝臟細胞脂質代謝混亂較為嚴重。AMPK能正向調控細胞自噬作用(autophagy)的反應，我們發現2 μm PS-MPs及100 nm PS-MPs會促進自噬作用，但大粒徑的PS-MPs對小鼠肝臟細胞所造成的毒性現象較為明顯，在24和48小時皆會誘導自噬作用的增加，以維持體內穩定。PS-MPs確實直接影響肝細胞中miR-122-5p及miR-33-5p表現下降，影響脂質代謝。同時，肝組織的RNA序列分析顯示，給予2 μm PS-MPs的組別有AMPK路徑活化及促使脂質生合成下降，脂質分解相關基因表現上升。細胞暴露於PS-MPs會使粒線體膜電位下降，並產生活性氧物質（ROS）。綜合上述實驗結果，不論粒徑大小的PS-MPs皆會影響粒線體的功能，造成細胞產生壓力，促進AMPK路徑的活化，並誘導autophagy路徑，影響脂質代謝平衡，並會使exosome的釋出量下降，而又以大粒徑的2 μm PS-MPs所造成的脂質代謝混亂及毒性較為顯著。

    Plastic particles with a diameter < 5 mm have been increasingly recognized as a global environmental threat and health hazard to human populations. The human can be exposed to microplastics (MPs) directly from the environment or through the food. Previous studies have demonstrated that MPs exposure could cause disruptions to energy and lipid metabolism but the underlying mechanism is still unclear. Liver is one of the largest metabolic organs and plays an important role in energy metabolism. In this study, we investigated whether MPs cause energy dysregulation through interfering lipid metabolism and activating AMP-activatedproteinkinase (AMPK)-Autophagy pathway. Furthermore, we also evaluated whether MPs affect the exosomes secretion because research into exosomes has swelled as their important role in the mediation of health and disease has been increasingly acknowledged. We used fluorescent and pristine polystyrene microplastics (PS-MPs) particles with two diameters (2 μm and 100 nm) in the study. In vivo experiments, fluorescent PS-MPs accumulated in liver that brightness gradually increased in 1, 4 hours, and decreased after 24 hours.Although both PS-MPs were excreted over time, PS-MPs may indeed be accumulated or stored in the liver. The mice treated PS-MPs decreased the relative liver weights, hepatic triglyceride(TG) levels, serum TG and total cholesterol(TCHO) levels. Histological staining of liver tissues showed that feature of small lipid droplets. Mice treated with PS-MPs for four and eight weeks. The liver tissueshowed the increased proteinexpression of p-AMPK-α. Both particle size of PS-MPs can reduced the mitochondrial membrane potential and produce reactive oxygen species (ROS), promote the activation of the AMPK-Autophagy pathway, and suppress miR-122-5p and miR-33-5p expression in liver tissue. When hepatocyte (AML-12 cell) exposed to PS-MPs, the balance of lipid metabolism was affected and accompanied by the decrease of exosomes release. Comparing both sizes of PS-MPs, we found that 2 μm PS-MPs caused more severe lipid metabolism disorder and toxicity than 100 nm PS-MPs.

    目錄 第一章、序論1 第二章、文獻回顧2 第一節、塑膠微粒(microplastic)的來源與毒性2 第二節、肝臟在代謝中扮演著重要的角色4 第三節、自噬作用(autophagy)對細胞內能量的調節5 第四節、MicroRNA（miRNA）與肝臟代謝機轉7 第五節、粒線體參與能量代謝8 第六節、外泌體（exosome）其生理功能與可能的影響作用9 第三章、研究目的12 第四章、研究材料與方法13 第一節、研究材料13 (一) 細胞株：13 (二) 儀器：13 (三) 試劑與耗材:14 第二節、研究方法與實驗步驟18 (一)聚苯乙烯-塑膠微粒(PS-MPs)的製備：18 (二)物化性分析方法：19 (三)動物實驗：19 (四)細胞實驗：22 (五)統計分析：27 第五章、研究架構28 第六章、研究結果30 第一節、聚苯乙烯塑膠微粒(PS-MPs)之物理化學特性30 第二節、PS-MPs在C57BL/6 小鼠器官中的分布30 第三節、PS-MPs誘導 C57BL/6 小鼠之可能的肝毒性31 (一) PS-MPs所影響小鼠血清生化值變化31 (二) PS-MPs所影響小鼠肝臟三酸甘油酯值變化32 (三)小鼠器官與H&E染色結果32 第四節、PS-MPs誘導之肝臟損傷機制32 (一)小鼠暴露PS-MPs後誘發脂質代謝變化32 (二)小鼠暴露PS-MPs後誘發自體吞噬效應33 (三)小鼠暴露PS-MPs後抑制miR-122及miR-33表現量33 (四) 利用RNA-seq分析，釐清複雜之肝臟損傷機制與RNA的變化34 第五節、小鼠正常肝臟細胞AML-12暴露PS-MPs之攝入情形34 第六節、探討細胞暴露PS-MPs後所誘發的粒線體膜電位改變35 第七節、探討細胞暴露PS-MPs後所誘發的脂質代謝變化36 第八節、探討細胞暴露PS-MPs後誘發的自體吞噬效應36 第九節、肝臟細胞暴露PS-MPs影響miR-122和miR-33基因表現量37 第十節、細胞暴露PS-MPs後所造成外泌體分泌影響37 第七章、討論39 第八章、結論與建議48 第九章、參考資料50 圖表目錄 圖一、MP的來源(Water Challenges of an Urbanizing World,2018)3 圖二、AMPK調節細胞代謝過程(Garcia and Shaw 2017)5 圖三、自噬作用機制(Ravanan et al. 2017)6 圖四、粒線體產生能量的機制(White 2001)9 圖五、外泌體（exosome）的生合成與釋放(Guo et al. 2017)11 表一、代謝相關組織重要的miRNA (Vienberg et al. 2017)8 Fig. 1. Characterization of PS-MPs.63 Fig. 2. Biofluorescence IVIS image of fluorescent carboxyl PS-MPs in mice liver.64 Fig. 3. The body weight during the study period.64 Fig. 4. Serum biochemistry parameters in C57BL/6 mice exposed to PS-MPs.65 Fig. 5. The hepatic triglyceride (TG) levels in C57BL/6 mice exposed to PS-MPs.65 Fig. 6. Histological staining of liver tissues showed that feature of small lipid droplets when mice exposed to 2 μm and 100 nm PS-MPs.66 Fig. 7. Western blotting for lipid metabolism and autophagy protein analysis of C57BL/6 mice liver exposed to 2 μm PS-MPs for 4 and 8 weeks.67 Fig. 8. Western blotting for lipid metabolism and autophagy protein analysis of C57BL/6 mice liver exposured to 100 nm PS-MPs for 4 and 8 weeks.68 Fig. 9. miR-122-5p and miR-33-5p expression levels were evaluated by real-time PCR in liver tissiue from C57BL/6 mice.69 Fig. 10. The RNA-sequencing analysis of liver tissues in C57BL/6 mice exposed to 2 μm PS-MPs for 8 weeks.71 Fig. 11. The cellular uptake of PS-MPs in AML-12 cell model.73 Fig. 12. Cytotoxicity induced by 2 μm and 100 nm PS-MPs. 74 Fig. 13. PS-MPs lead to AML-12 cells mitochondrial membrane potential (MMP) loss.76 Fig. 14. Treatment with the PS-MPs lead to superoxide generation in AML-12 cells.77 Fig. 15. Effects on hepatic lipid accumulation and protein expression in AML-12 cells treated with 2 μm PS-MPs.79 Fig. 16. Effects on hepatic lipid accumulation and protein expression in AML-12 cells treated with 100 nm PS-MPs.81 Fig. 17. Autophagy levels of AML-12 cells treated with 2 μm PS-MPs.83 Fig. 18. Autophagy levels of AML-12 cells treated with 100 nm PS-MPs.85 Fig. 19. miR-122-5p and miR-33-5p expression levels were changed when PS-MPs exposed to AML-12 cells.86 Fig. 20. Characterization of exsomes purified from AML-12 conditioned medium.88 Fig. 21. Double labeling with calcein-AM and CD63-APC ensures precise enumeration of exosomes by flow cytometry.88 Table. 1. Genes related to fatty acid metabolism 72 Fig. S1. The relative liver weight (liver weight/final body weight ×100) of mice treated with ddH2O (control), 0.1 mg/day (low) and 0.2 mg/day (high) in 100 nm PS-MPs groups for 4 weeks and 8 weeks.89 Fig. S2. The cellular uptake of 2 μm PS-MPs in AML-12 cell model.90

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