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系統識別號 U0026-0812200915084715
論文名稱(中文) 探討以NNK為起始劑TCDD為腫瘤促進劑所導致的肺腫瘤生成過程中雌素二醇可能之角色
論文名稱(英文) Investigate the possible role of estradiol in NNK-initiated, TCDD- promoted lung tumorigenesis
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 97
學期 2
出版年 98
研究生(中文) 張櫸壅
研究生(英文) Chu-Yung Chang
電子信箱 s7694106@mail.ncku.edu.tw
學號 s7694106
學位類別 碩士
語文別 中文
論文頁數 84頁
口試委員 召集委員-何元順
口試委員-張惠華
口試委員-張育嘉
口試委員-林嬪嬪
指導教授-王應然
中文關鍵字 A /J小鼠  NNK  雌素二醇  2,3,7,8-四氯二聯苯戴奧辛 
英文關鍵字 estradiol  A/J mice  2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)  NNK 
學科別分類
中文摘要 2,3,7,8-四氯二聯苯戴奧辛(2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD )是環境中常見的污染物質,研究顯示TCDD對於囓齒類動物具有很高毒性。在Seveso的二十年流行病學追蹤研究中,發現TCDD會增加罹患肺癌的風險,尤其是女性有更高的罹患風險(RR = 1.3, 95% CI: 1.2- 4.6)。然而,TCDD誘發肺癌的機制,至今仍不清楚。在動物實驗的文獻指出TCDD會增加母鼠呼吸系統罹癌的發生率,而公鼠卻沒有相類似的情形。TCDD造成的肺部傷害也發現有性別上的差異情形。另外,在相關的文獻亦指出摘除卵巢和沒有摘除卵巢的老鼠給予TCDD後,摘除卵巢的組別具有較低的肝腫瘤發生率。因此推測,卵巢賀爾蒙(雌素二醇)在TCDD促進的肺腫瘤機制中可能扮演著重要的角色。本篇研究主要的目的是在探討雌素二醇是否為TCDD促進肺腫瘤發生的機制之一,實驗利用A/J雌性小鼠,以摘除卵巢的模式來探討雌素二醇的作用。將小鼠分為摘除卵巢及沒有摘除卵巢的組別,實驗第一週先施打腫瘤起始劑NNK,第二週開始施打雌素二醇或玉米油每兩天一次,並於第三週起連續施打TCDD 4週,最後在7週以及24週犧牲動物。實驗結果發現不論在公鼠或是母鼠NNK合併TCDD組別中,肺腫瘤發生率都高於公鼠和母鼠的控制組。另外,在摘除卵巢無持續施打雌素二醇的組別中和無摘除卵巢相比較,其腫瘤發生率皆有明顯的下降。但在摘除卵巢持續施打雌素二醇的組別中,卻發現到NNK組的肺腫瘤發生率明顯高於NNK合併TCDD的組別。由此可知,TCDD和雌素二醇可能都扮演著肺腫瘤促進的角色。在以NNK為起始劑的致癌模式中,TCDD扮演著抑制雌素二醇的角色。另外,在7週分子機制的研究方面,發現TCDD和雌素二醇經由MAP Kinase訊息傳遞路徑,調控NFκB的路徑活化,進而造成發炎反應和細胞增生的現象。TCDD和雌素二醇經由造成發炎反應和細胞增生的方式促進腫瘤的發生。
英文摘要 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is an ubiquitous environment- al contaminant and highly toxic to several rodent species. During the 20-year period following the Seveso showed TCDD could increase risk of lung cancer, notably among women (RR = 1.3, 95% CI: 1.2-4.6). In animal studies, TCDD-induced lung lesions appeared to be gender dependent, with predominant increase of the incidence of respiratory tract cancers in female but not in male rat. In TCDD studies, hepatic tumor incidence was lower in TCDD-treated ovariectomized (OVX) female rats compared to TCDD-treated sham-operated rats. Thus, we predict that ovarian hormones (estradiol) may be involved in the process of TCDD-induced lung tumorigenesis. The object of this study is to test the hypothesis that whether ovarian hormones (estradiol) is involved in the two-stage lung tumorigenesis promoted by TCDD in female rodent. For this proposal, a two-stage model for lung tumorigenesis sham-operated or OVX- female A/J mice were applied to investigate the effect of ovarian hormones. In in vivo study, OVX- or sham-operated mice were given tumor initiator NNK at week-1 of experiment, received subcutaneous (s.c.) injections of estradiol or corn oil every two days start from week-2 until the end of experiment, given 4 times weekly of TCDD at week-3 and sacrificed at 7 weeks and 24 weeks of experiment. Treatment of female and male mice with NNK alone or combination with TCDD resulted in increased lung tumor incidence compared with female and male control mice. In addition, lung tumor incidence was lower in OVX female mice compared to female mice treated with NNK and TCDD. Whereas, treatment of OVX female mice with NNK and estradiol resulted in a significant increased lung tumor incidence compared with treatment of female mice with combination of NNK, TCDD and estradiol.Hence, TCDD and estradiol both play important role in tumor promotion, nevertheless, inhibition of estradiol promoted tumor incidence by TCDD in NNK-initiated lung tumorigenesis.Short-term mechanistic studies indicated that TCDD and estradiol affect inflammation and cell proliferation by activatin of Mitogen-activated protein kinases (MAPK) pathways and NF-κB pathways at 7 weeks.Thus, we concluded that TCDD and estradiol promote NNK-initiated lung tumorigenesiscould be through enhanced inflammmation and cell proliferation.
論文目次 第一章 序論 1
第二章 文獻探討 2
第一節 肺癌 2
第二節 戴奧辛簡介 3
第四節 雌荷爾蒙 9
第五節 化學致癌 12
第六節 MAPK路徑 16
第三章 研究目的 18
第五章 研究材料與方法 24
第六章 結果 38
第一節 長期24週動物實驗 38
第二節 短期7週動物實驗 40
第三節 血清中7週和24週CYTOKINE的改變 40
I.血清中7週和24週TNF-的改變 40
II.血清中7週和24週IL-2的改變 41
III.血清中7週和24週TGF-1的改變 43
第四節 7週肺部組織切片的改變 45
第五節 7週肺部組織的蛋白質表現 45
第七章 討論 48
第八章 結論 54
第九章 參考文獻 55
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