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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 劉興華(Shing-Hwa Liu) | |
| dc.contributor.author | Shih-Chun Sun | en |
| dc.contributor.author | 孫詩淳 | zh_TW |
| dc.date.accessioned | 2021-06-07T23:42:24Z | - |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-25 | |
| dc.identifier.citation | 1. Holger M. Koch, Bernd Rossbach, Hans Drexler, and Jurgen Angerer. Internal exposure of the general population to DEHP and other phthalates—determination of secondary and primary phthalate monoester metabolites in urine Environmental Research 2003; 93: 177–185.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/16627 | - |
| dc.description.abstract | 鄰苯二甲酸二(2-乙基己基)酯(di(2-ethylhexyl) phthalate, DEHP)為臺灣最為廣泛使用之塑化劑，作用為增加塑膠製品之彈性及延展性，常用於醫療器材、食品包裝、建材及玩具表層塗漆。研究指出塑化劑為內分泌干擾物(Endocrine disruptor chemicals, EDCs)，EDCs為類雌激素化學物質，會干擾生物體內內分泌系統之正常作用。其中，目前已知骨代謝為一動態平衡，由造骨細胞之骨再塑作用及噬骨細胞之再吸收作用相互調節，而此平衡由許多荷爾蒙共同調控。其中造骨細胞由骨髓中所含之間葉性幹細胞(mesenchymal stem cells, MSCs)分化而成，MSCs經系統性調控亦可分化為脂肪細胞。文獻指出MSCs分化為造骨細胞及脂肪細胞間存在一平衡，若失調會引起骨質疏鬆及其他疾病。暴露於EDCs會干擾荷爾蒙調節作用，可能對細胞分化平衡產生影響，進一步引起疾病產生。因此本研究欲探討DEHP及其代謝物鄰苯二甲酸(2-乙基己基)酯(mono(2-ethylhexyl) phthalate, MEHP)對MSCs分化為造骨細胞及脂肪細胞之影響及其作用機轉。細胞實驗中以五週齡之雄性ICR小鼠犧牲後分離股骨及脛骨骨髓中之MSCs培養，培養過程以誘導造骨細胞分化之培養液進行骨細胞分化實驗，過程中分別處理0、10、25、50、100 μM之DEHP，暴露後以MTT assay確認細胞毒性，結果顯示DEHP並不會影響細胞存活。另外於暴露DEHP後第7天測量鹼性磷酸酶活性、第21天時以Alizarin red染色觀察骨礦物化，結果顯示造骨細胞分化能力明顯受到抑制。在第14天時，以Real time-qPCR觀察RNA表現，發現骨分化相關基因ALP, osteocalcin及runx2表現下降。動物實驗部分以五週齡之雄性ICR小鼠，以10、100 mg/kg/day之DEHP管餵八週，犧牲後分離MSCs培養，分別以誘導造骨細胞及脂肪細胞分化之培養液培養，結果顯示管餵DEHP後骨分化指標鹼性磷酸酶活性及骨礦物化程度被抑制，與細胞實驗結果相符。另外，以微米級電腦斷層掃描造影系統觀察脛骨內骨小梁組織型態之變化，結果發現管餵DEHP 100 mg/kg/day的組別骨礦物質密度、相對骨體積及骨小梁數量皆顯著下降。同時，在管餵DEHP之組別看到促進脂肪細胞分化之現象，然而在細胞實驗中處理DEHP並未對脂肪細胞分化產生影響。接著，我們進一步觀察DEHP之代謝物MEHP於MSCs分化所造成之影響。實驗結果顯示MEHP亦會抑制造骨細胞分化，此外MEHP會促進脂肪細胞之分化。最後，我們對DEHP於分化過程中作用之機轉進行探討，結果發現DEHP抑制造骨細胞分化的同時，Wnt1、β-catenin及constitutive androstane receptor (CAR)之RNA表現下降，而促進脂肪細胞分化之peroxisome proliferator-activated receptor gamma (PPAR-γ)之RNA表現上升。綜合以上結果，DEHP及其代謝物MEHP皆會抑制造骨細胞分化，然而DEHP需經代謝為MEHP才會促進脂肪細胞分化。DEHP會經由抑制Wnt1/β-catenin pathway進一步抑制下游成骨細分化相關基因，此過程可能經由CAR及PPAR-γ調控。由結果可知DEHP及MEHP會抑制造骨細胞分化及促進脂肪細胞分化，改變兩者間平衡狀態，可能會導致骨質疏鬆及其他相關疾病。未來將研究DEHP及其代謝物MEHP對造骨細胞及脂肪細胞分化間平衡改變之詳細機轉，並對CAR及PPAR-γ所扮演之調控角色進一步探討。 | zh_TW |
| dc.description.abstract | Di(2-ethylhexyl) Phthalate (DEHP), the most widely used phthalate in Taiwan, is added in polyvinyl chloride plastics to increased flexibility. DEHP is commonly used in medical devices, food package, architectural materials, and surface coating. Besides, DEHP is a well-known endocrine-disrupting chemicals (EDCs). EDCs are estrogenic industrial compound that can disrupt normal hormone signaling systems, which raised considerable concern in recent years. Bone microenvironment is a complex dynamic equilibrium between osteoclasts and osteoblasts and is modulated by a wide variety of hormones. Moreover, factors promote adipogenesis not only lead to fatty marrow but also decrease osteoblastogenesis, and eventually affect bone formation. Therefore, we investigate the effects and mechanisms of DEHP and its metabolites, mono(2-ethylhexyl) phthalate (MEHP),on osteoblast and adipocyte differentiation from mouse bone marrow-derived MSCs. Bone marrow-derived mesenchymal stem cells (MSCs) were isolated from normal mice and DEHP-gavaged mice; the former is cultured with DEHP to evaluate the effects on differentiation and the latter is cultured without DEHP to examine whether 8-week DEHP exposure affect differentiation ability of MSCs. At the end of the experiments, Alizarin Red S stain was conducted to observe mineralization and alkaline phosphatase (ALP) activity were measured to evaluate osteoblast differentiation. The oil deposit formation through adipocyte differentiation was evaluated through Oil Red O stain. Besides, the RNA expression of the osteoblast markers, Runx2 and osteocalcin, and adipogenesis marker, PPAR-γ, were detected. The changes in bone morphology were observed by micro-computed tomography (micro-CT). MTT assay showed that 10-100 μM DEHP have no cytotoxicity to MSCs. After DEHP treatment in vitro, ALP activity and Alizarin Red S stain indicated that osteoblast differentiation was inhibited. Expression of osteoblast- related genes, osteocalcin and runx2, decreased in Real-time PCR results. Expression of Wnt1 and s-catenin were markedly decreased, which indicated that DEHP inhibited osteoblastogenesis through Wnt/s-catenin pathway. The expression of PPAR-γ increased, however the Oil Red O stain showed that DEHP have no effect on adipocyte differentiation. Moreover, the inhibition of ALP activity, Alizarin Red S stain, bone mineral density and osteoblast marker expression revealed that osteoblastogenesis potential decreased after DEHP gavage administration. Reciprocally, the enhancement of Oil Red O stain and the expression of PPAR-γ showed that adipogenesis potential increased. Further, DEHP metabolite, MEHP, had same effects on osteoblast differentiation from MSCs as DEHP. Though DEHP showed no effect on adipogenesis in MSCs in vitro, MEHP enhanced adipogenesis in MSCs. The present study suggested that DEHP decreased osteoblastogenesis through Wnt/s-catenin pathway and which would not promote adipogenesis unless metabolized to MEHP. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T23:42:24Z (GMT). No. of bitstreams: 1 ntu-103-R01447005-1.pdf: 2226898 bytes, checksum: 610d65f0c1953d29156d68cef969932f (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 碩士學位論文口試委員會審定書--------------------------------------------------------------I
致謝-------------------------------------------------------------------------------------------------II 中文摘要------------------------------------------------------------------------------------------III Abstract --------------------------------------------------------------------------------------------V Abbreviations ---------------------------------------------------------------------------------VIII CHAPTER I INTRODUCTION 1. DEHP------------------------------------------------------------------------------------------1 2. Endocrine disrupting chemicals----------------------------------------------------------4 3. Stem cells--------------------------------------------------------------------------------------6 4. Osteoblast differentiation(Osteoblastogenesis) ---------------------------------------7 5. Adipocyte differentiation(Adipogenesis) ---------------------------------------------11 6. Balance between osteoblastogenesis and adipogenesis-----------------------------13 7. Aims -----------------------------------------------------------------------------------------16 8. Experimental design----------------------------------------------------------------------17 CHAPTER II MATERIALS AND METHODS--------------------------------------18 CHAPTER III RESULTS-----------------------------------------------------------------24 CHAPTER IV DISCUSSION-------------------------------------------------------------29 CHAPTER V CONCLUSION AND FUTURE PERSPECTIVE----------------33 CHAPTER VI FIGURES -----------------------------------------------------------------35 CHAPTER VII REFERENCES ----------------------------------------------------------52 | |
| dc.language.iso | en | |
| dc.subject | 間葉性幹細胞 | zh_TW |
| dc.subject | 鄰苯二甲酸二(2-乙基己基)酯 | zh_TW |
| dc.subject | 鄰苯二甲酸(2-乙基己基)酯 | zh_TW |
| dc.subject | 脂肪分化 | zh_TW |
| dc.subject | 造骨細胞分化 | zh_TW |
| dc.subject | 內分泌干擾物 | zh_TW |
| dc.subject | mesenchymal stem cells | en |
| dc.subject | endocrine disrupting chemical | en |
| dc.subject | osteoblastogenesis | en |
| dc.subject | adipogenesis | en |
| dc.subject | DEHP | en |
| dc.subject | MEHP | en |
| dc.title | 探討塑化劑鄰苯二甲酸(2-乙基己基)酯及其代謝物對小鼠骨髓間質幹細胞分化為造骨細胞及脂肪細胞之影響 | zh_TW |
| dc.title | Effects of Di(2-ethylhexyl) Phthalate and Its Metabolite on Osteoblast and Adipocyte Differentiation from Mouse Bone Marrow-derived Mesenchymal Stem Cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蕭水銀(Shoei-Yn Shiau),姜至剛(Chih-Kang Chiang),楊榮森(Rong-Sen Yang) | |
| dc.subject.keyword | 鄰苯二甲酸二(2-乙基己基)酯,鄰苯二甲酸(2-乙基己基)酯,間葉性幹細胞,脂肪分化,造骨細胞分化,內分泌干擾物, | zh_TW |
| dc.subject.keyword | DEHP,MEHP,mesenchymal stem cells,adipogenesis,osteoblastogenesis,endocrine disrupting chemical, | en |
| dc.relation.page | 64 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2014-07-25 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-103-1.pdf 未授權公開取用 | 2.17 MB | Adobe PDF |
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