請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17490
標題: | 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 Effects of di(2-ethylhexyl) phthalate on insulin function and blood glucose regulation |
作者: | Hsiao-Jung Chang 張曉榕 |
指導教授: | 劉興華 |
關鍵字: | 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, Di(2-ethylhexyl) phthalate,DEHP,plasticizer,insulin secretion,metabolic syndrome,glucose tolerance,control of blood sugar, |
出版年 : | 2013 |
學位: | 碩士 |
摘要: | 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。 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. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17490 |
全文授權: | 未授權 |
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-102-1.pdf 目前未授權公開取用 | 5.23 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。