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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 劉興華 | |
dc.contributor.author | Hsiao-Jung Chang | en |
dc.contributor.author | 張曉榕 | zh_TW |
dc.date.accessioned | 2021-06-08T00:16:08Z | - |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-07-29 | |
dc.identifier.citation | 1. Agency for Toxic Substances and Disease Registry (ATSDR). (2002). Toxicological Profile for Di(2-ethylhexyl) phthalate (DEHP).
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Toda N and Nakanishi-Toda M. (2007). Nitric oxide: ocular blood flow, glaucoma, and diabetic retinopathy. Prog Retin Eye Res 26, 205-238. 35. Toyosawa K, Okugawa K, Teranishi Y, Tanaka K and Matsuoka N. (2003). Overexpression of the peroxisome proliferator activated receptor α or the human c-Ha-ras transgene is not involved in tumorigenesis induced by di(2-ethylhexyl) phthalate in rasH2 mice. Cancer Lett 192, 199-203. 36. Tranfo G, Caporossi L, Paci E, Aragona C, Romanzi D, De CC, De RM, Capanna S, Papaleo B and Pera A. (2012). Urinary phthalate monoesters concentration in couples with infertility problems. Toxicol Lett 213, 15–20. 37. Voss C, Zerban H, Bannasch P and Berger MR. (2005). Lifelong exposure to di-(2-ethylhexyl)-phthalate induces tumors in liver and testes of Sprague-Dawley rats. Toxicology 206, 359-371. 38. Whyatt RM, Adibi JJ, Calafat AM, Camann DE, Rauh V, Bhat HK, Perera FP, Andrews H, Just AC, Hoepner L, Tang D and Hauser R. (2009). Prenatal di(2-ethylhexyl)phthalate exposure and length of gestation among an inner-city cohort. Pediatrics 124, e1213–e1220. 39. Wolff MS, Teitelbaum SL, Pinney SM, Windham G, Liao L, Biro F, Kushi LH, Erdmann C, Hiatt RA, Rybak ME and Calafat AM. (2010). Investigation of relationships between urinary biomarkers of phytoestrogens, phthalates, and phenols and pubertal stages in girls. Environ Health Perspect 118, 1039–1046. 40. World Health Organization (WHO). (2003). Di(2-ethylhexyl)phthalate in Drinking-water. 41. Yang J, Hauser R and Goldman RH. (2013). Taiwan food scandal: The illegal use of phthalates as a clouding agent and their contribution to maternal exposure. Food Chem Toxicol 58, 362-368. 42. Yang R and Trevillyan JM. (2008). c-Jun N-terminal kinase pathways in diabetes. Int J Biochem Cell Biol 40, 2702-2706. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17490 | - |
dc.description.abstract | 鄰苯二甲酸二(2-乙基己基)酯(DEHP)被廣泛用於聚氯乙烯產品中,如塑料玩具、裝潢建材、醫療器具、美妝產品、化學藥劑及食品保鮮包裝等,做為塑化劑以增加塑膠製品韌性和延展性。一般人類的接觸途徑為經食物或飲用水口服、經呼吸道吸入、皮膚接觸、藉由醫療行為過程暴露、經母體哺乳、胎盤血液交換等。已知DEHP造成生殖毒性、影響神經發育、過敏、可能造成DNA損傷、染色體數目改變或缺失及肝臟腫瘤產生,但因目前對人類致癌證據不足,國際癌症研究中心(IARC)列為Group 2B,即可能為人類致癌物質。目前的醫學研究發現,同一病患身上常合併多種危險因素,如血壓較高、空腹血糖上升、高三酸甘油脂血症與偏低的高密度脂蛋白膽固醇和肥胖,如果符合上面所列危險因子的一項,稱為「代謝症候群高危險群」。代謝症候群患者易併發或死於心血管疾病,也有較高風險患糖尿病。近年來關於DEHP對於胰島細胞及糖尿病產生的影響相關報導並不多,但已有研究報導指出,DEHP對大鼠子代會降低其胰島素分泌,可能導致其在成年期產生胰島素抵抗性;臨床研究報導指出若尿液中DEHP之代謝產物(如MEHP及其他二級代謝產物)較多者,患糖尿病的機率會比DEHP代謝物少的人高,然而對於DEHP如何造成代謝異常及影響胰島素分泌仍未明瞭。因此本實驗研究目的為探討於不同劑量下的DEHP對於beta-cells胰島素分泌功能影響與細胞毒性,並研究其作用機轉;另外在本實驗中也進行不同週數及性別的活體(in vivo)實驗,分析DEHP造成血糖與血脂調控的影響,以期進一步釐清DEHP可能影響人體血糖調控的過程。在我們的實驗中使用大鼠胰島細胞RIN-m5F,以DEHP 10及100 microM處理RIN-m5F 24、72及96小時後,於高葡萄糖環境下(20 mM glucose)刺激細胞分泌胰島素,結果在24小時處理10及100 microM DEHP之組別皆顯著促進RIN-m5F分泌胰島素,且低劑量組結果隨處理時間增加胰島素分泌。接著以西方點墨法(Western blot analysis)分析,結果顯示RIN-m5F細胞株在暴露DEHP的環境下會誘導IRS-1、ERK及Akt的磷酸化表現,並且於高劑量組觀察到JNK、p38及ERK的磷酸化都有明顯增加的情況。另外我們也進行動物實驗,使用分別使用五週齡雄小鼠、三週齡雄性與雌性小鼠及懷孕母鼠與其子代等三種動物模式。在五週大雄鼠上的實驗結果顯示,長時間持續性暴露DEHP會造成小鼠動物實驗模式下體內高血糖情況產生,影響實驗小鼠的血糖調控功能,而此情形可能是因DEHP造成胰島細胞凋亡,減少胰島細胞功能,使胰島素分泌下降,最終導致體內葡萄糖利用率降低,而產生高血糖現象、葡萄糖耐受性不良結果及血中三酸甘油脂偏高。除了觀察DEHP對成熟雄性小鼠的影響外,我們也使用剛離乳約3週大的雄性及雌性小鼠來進行實驗,處理高劑量DEHP的雄性小鼠其血糖較控制組高,也有葡萄糖耐受性不良之結果及血中三酸甘油脂偏高,但雌性小鼠則皆無差異,顯示DEHP對雄鼠血糖調節影響較大。最後,我們於母鼠懷孕後期開始餵食高劑量DEHP,並持續餵食母鼠直到子代斷奶(3週齡),但不論母鼠或子代,DEHP對其空腹血糖影響不大;不過母鼠於孕期開始暴露高劑量DEHP後,其子代血液中胰島素量及胰島素阻抗值皆顯著增加,且此情況無性別差異。綜合上述結果,DEHP其增加細胞胰島素分泌、影響血糖調控的可能路徑是經由活化IRS-1、ERK與Akt而調控;其造成的細胞毒性可能是藉由JNK、p38及ERK的活化所控制。此外,動物實驗證實DEHP影響實驗小鼠的血糖調控功能,產生高血糖現象、葡萄糖耐受性不良結果及血中三酸甘油脂偏高,顯示長期暴露高劑量DEHP會可能促使成代謝症候群高危險群分子。 | zh_TW |
dc.description.abstract | Di(2-ethylhexyl) phthalate (DEHP) is widely used in PVC products, such as plastic toys, decoration materials, medical equipment, beauty products, chemicals and food packaging, as a plasticizer to increase the toughness and ductility of plastic products. Human exposure usually through food or water, inhalation, skin contact, medical practices and breastfeed. DEHP causes reproductive toxicity, neurotoxicity, allergies, DNA damage, chromosome damage and deletion and liver tumors, the International Center for Research on Cancer (IARC) as a Group 2B, which may be classified human carcinogen. The patients who often associated with multiple risk factors, such as hypertension, hyperglycemia, hypertriglyceridemia, low high-density lipoprotein cholesterol and obesity, called metabolic syndrome. Patients with metabolic syndrome have a higher risk of diabetes.According the reports, women with higher levels of phthalate metabolites (ΣDEHP) had an increased odds of diabetes compared with women with the lowest levels of these phthalates. DEHP will reduce secretion of insulin in rats offspring, and it may create insulin resistance in adulthood, but its mechanism is still unclear. The aim of this study is to discuss the effects of DEHP on insulin function and blood glucose regulation.In this study, DEHP treatment of pancreatic beta-cell line (RIN-m5F) was increased insulin secretion, and expressed phosphor IRS-1, phosphor Akt and phosphor ERK. DEHP also increase phosphorylation of JNK, p38, it may the reason of DEHP caused beta-cell apoptosis.We observed that 12 weeks oral exposure of DEHP (10, 25 and 100 mg/kg/day) to 3 and 5 weeks old male mice, DEHP significantly increase blood sugar, decrease plasma insulin and islet area, elevation of serum triglyceride and effect of glucose intolerance. On the other hand, we also treat 100 mg/kg/day of DEHP to pregnant female mice, until both male and female pups were weaned on postnatal day (PND) 21, all the offspring’s plasma insulin and insulin resistant were significantly increase.In conclusion, these results indicate that DEHP increased insulin secretion, and expressed phosphor IRS-1, phosphor Akt and phosphor ERK, DEHP also increase phosphorylation of JNK, p38 and it may the reason of DEHP caused beta-cell apoptosis. Moreover, DEHP significantly increase blood sugar, decrease plasma insulin and islet area, elevation of serum triglyceride and effect of glucose intolerance. It is show long-term exposure of high doses DEHP would likely induce a high risk of metabolic syndrome. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T00:16:08Z (GMT). No. of bitstreams: 1 ntu-102-R00447005-1.pdf: 5357504 bytes, checksum: f7e7821b9f97e581060d0301e2287e3b (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 口試委員審定書 iii
誌謝 iv 中文摘要 v Abstract vii 縮寫表 ix 第一章 1 導論 1 1.1. 鄰苯二甲酸二(2-乙基己基)酯(bis(2-ethylhexyl) phthalate 或 di(2-ethylhexyl) phthalate, DEHP)之簡介 1 1.2. 代謝症候群及糖尿病與DEHP之研究背景 3 1.3. 影響胰島素分泌(insulin secretion)可能的分子機制 5 1.3.1. 有絲分裂活化蛋白質激酶家族(MAPK famaily)的角色 6 1.3.2. PI3K(phosphoinositide 3-kinase)/Akt 路徑 6 第二章 7 研究目的 7 第三章 8 材料與方法 8 3.1. 細胞實驗 8 3.1.1. 細胞培養 8 3.1.2. 細胞存活率實驗(MTT assay) 8 3.1.3. 胰島素分泌測量實驗 9 3.1.4. 蛋白質分析-西方點墨法(Western blot analysis) 9 3.1.5. 實驗數據統計 12 3.2. 動物實驗 13 3.2.1. 實驗動物 13 3.2.2. 飼養環境 13 3.2.3. 藥物處理方法及實驗設計組別 13 3.2.4. 血糖值測定 13 3.2.5. 口服葡萄糖耐受性測試(Oral Glucose Tolerance Test, OGTT) 14 3.2.6. 胰島素耐受性測試(Insulin Tolerance Test, ITT) 14 3.2.7. 血清中胰島素分泌濃度測量實驗 14 3.2.8. 組織病理切片製作程序 15 3.2.9. 組織染色(蘇木紫-伊紅染色法,Hematoxylin-Eosin stain) 17 3.2.10. 胰島面積計算 17 3.2.11. DNA 斷裂端標記試驗(Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling, TUNEL assay) 17 3.2.12. 實驗數據統計 19 第四章 20 實驗結果 20 4.1. DEHP與MEHP對大鼠胰島細胞株RIN-m5F的細胞毒性影響及其劑量選擇 20 4.2. DEHP對RIN-m5F細胞株胰島素分泌、細胞毒性之影響及其作用機轉 21 4.2.1. DEHP對RIN-m5F細胞株胰島素分泌之影響 21 4.2.2. DEHP對IRS-1、ERK及Akt磷酸化的影響 21 4.2.3. DEHP活化MAPK family 21 4.3. DEHP對活體(in vivo)的影響 23 4.3.1. 口服餵食DEHP對小鼠血糖值的影響 23 4.3.2. 口服餵食DEHP對小鼠血液中胰島素含量之影響 23 4.3.3. DEHP對小鼠口服葡萄糖耐受性及胰島素耐受性之影響 23 4.3.4. DEHP對小鼠血液生化值的影響 24 4.3.5. DEHP對小鼠胰臟組織變化影響 24 4.3.6. DEHP對小鼠胰島細胞凋亡(apoptosis)的影響 25 4.3.7. DEHP對不同性別離乳幼鼠的影響 25 4.3.8. 孕期暴露DEHP對子代的影響 25 第五章 27 結果討論 27 5.1. DEHP促進RIN-m5F細胞株分泌及調控胰島素的角色 27 5.2. DEHP對活體(in vivo)影響及其角色 28 參考文獻 29 圖表 34 | |
dc.language.iso | zh-TW | |
dc.title | 探討塑化劑鄰苯二甲酸二(2-乙基己基)酯對胰島素功能與血糖調節之影響 | zh_TW |
dc.title | Effects of di(2-ethylhexyl) phthalate on insulin function and blood glucose regulation | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蕭水銀,楊榮森 | |
dc.subject.keyword | 鄰苯二甲酸二(2-乙基己基)酯,塑化劑,胰島素分泌,代謝症候群,葡萄糖耐受性,血糖調控, | zh_TW |
dc.subject.keyword | Di(2-ethylhexyl) phthalate,DEHP,plasticizer,insulin secretion,metabolic syndrome,glucose tolerance,control of blood sugar, | en |
dc.relation.page | 59 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2013-07-30 | |
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 |
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