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標題: 探討雌性激素受體與芳香族碳氫化物受體間訊息傳遞之交互作用
Investigation of the interactions between estrogen receptor alpha and aryl hydrocarbon receptor signaling pathway
作者: 洪珮慈
Hung, Pei-Tzu
關鍵字: human breast cancer cells;人類乳腺細胞;olycyclic aromatic hydrocarbons;estrogen receptor alpha;aryl hydrocarbon receptor;多環芳香族碳氫化合物;雌性激素受體;芳香族碳氫化物受體
出版社: 環境工程學系所
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多環芳香族碳氫化合物(polycyclic aromatic hydrocarbons, PAHs) 為常見的環境污染物質,且為已知之人類致癌物質。累積研究證據顯示,PAHs亦為荷爾蒙干擾物質,分別具有促進雌性激素(estrogenic)及抗雌性激素(anti-estrogenic)之特性,本研究目的為探討PAHs物質,包括naphthalene (Nap)、1-naphthol (1-NT)、2-naphthol (2-NT)、Benzo[a]pyrene (BaP)、以及鹵化芳香族碳氫化合物(halogenated aromatic hydrocarbons, HAHs)中的2,3,7,8-tertachlorodibenzo-p-dioxin (TCDD),於人類乳癌細胞之雌性激素干擾效應,以及對芳香族碳氫化物受體(aryl hydrocarbon receptor, AhR)與雌性激素受體(estrogen receptor α, ERα)間之訊息交叉 (cross-talk) 之影響。
本研究使用人類乳癌細胞株T47D-KBluc,此細胞株具有雌性激素受體α以及ERE (estrogen-responsiveelements)-promoter-luciferase reporter之轉殖基因。研究中分別利用細胞增生、指標基因及基因表現分析,來了解各種PAHs及TCDD之雌性激素干擾效應。首先第一部分探討促進雌性激素效應,並了解與AhR鍵結能力之強弱是否有關。其中與AhR鍵結能力之強弱為Nap第二部分探討抗雌性激素效應,並了解與AhR鍵結能力強弱之關聯。於cell proliferation assay與reporter gene assay之研究結果均顯示,Nap (10-4 M)共同添加E2(10-9 M)並無雌性激素干擾效應,而BaP (10-5 M)與TCDD (10-8、10-9 M)共同添加E2皆會產生抗雌性激素效應。此二分析方法結果一致,並證實此抗雌性激素效應與AhR鍵結能力之強弱具有相關。
最後,第三部分利用real-time RT-PCR assay探討TCDD與BaP暴露於人類乳癌細胞株T47D-KBluc,是否會誘發基因表現的改變,而這些基因表現的調控是否與ERα、AhR之間的訊息交叉(Cross-talk)有關。在「ERα調節AhR之作用」的部分,當添加ERα之抑制劑ICI 182,780後,E2之抑制TCDD或BaP誘發之CYP1A1表現將可被阻斷。因此ERα確實具有干擾AhR之基因調控的能力。在「AhR調節ERα之作用」的部分,當添加AhR抑制劑3'',4''- dimethoxyflavone後,TCDD之抑制E2所誘發之PR表現亦可被阻斷,反之BaP並不明顯,其機制尚待釐清。但由TCDD之結果顯示AhR確實具有干擾ERα之基因調控的能力,且具有cross-talk之可能。
綜合以上所述,在人類乳癌細胞株T47D-KBluc中,model compounds所產生之雌性激素之促進與拮抗效應均與AhR鍵結能力之強弱具有相關聯,而此機制可能是經由AhR與ERα間之cross-talk所致。

Polycyclic aromatic hydrocarbons (PAHs) are important classes of chemical carcinogens that are widespread in the environment. The primary purpose of this research is to examine the potential of PAHs, including naphthalene (Nap), 1-naphthol (1-NT), 2-naphthol (2-NT), Benzo[a]pyrene (BaP), and the halogenated aromatic hydrocarbons (HAHs), 2,3,7,8-tertachlorodibenzo-p-dioxin (TCDD), to mediate the estrogen receptor-dependent induction of abnormal cell proliferation and reporter gene expression in human T47D-KBluc breast cancer cells. We also investigated the effects of aryl hydrocarbon receptor (AhR) and estrogen receptor (ERα) cross-talk.
T47D-KBluc human breast cancer cells, which naturally express estrogen receptor alpha, were stably transfected with a triplet ERE (estrogen-responsive elements)-promoter-luciferase reporter gene construct. The first part of this research was to investigate the relationship between the extent of estrogenic activity of the selected model compounds and their corresponding AhR binding affinity. Results indicated that Nap, BaP, and TCDD did not exhibit estrogenic activity in T47D-KBluc cells as measured by cell proliferation assay. In contrast, BaP(10-5 M) and TCDD(10-8 M) but not Nap(10-4 M) display estrogenic effects in T47D-KBluc cells as determined by the reporter gene assay. We concluded that the estrogenic activity of the selected model compounds was associated with their respective AhR binding affinity.
The second part of this study was to investigate the relationship between the antiestrogenic activity of the model compounds and their corresponding AhR binding affinity. Result indicated that Nap (10-4 M) did not exhibit antiestrogenic activity in the presence of E2(10-9 M) in T47D-KBluc cells. In contrast, co-treatment of BaP (10-5 M) or TCDD (10-8; 10-9 M) with E2 displayed antiestrogenic activity in T47D-KBluc cells as measured by the cell proliferation assay and by the reporter gene assay. This evidence suggests that that the antiestrogenic activity of the model compounds correlates with their corresponding AhR binding affinity.
The third part of this study was to examine the effects of AhR and ERα cross-talk on the TCDD- and BaP-mediated altered gene expression by using the real-time RT-PCR method. Results indicated that ERα modulated the AhR-dependent gene expression in human T47D-KBluc breast cancer cells. ICI 182,780, an ERα inhibitor, completely blocked the E2-mediated down regulation of CYP1A1 gene expression induced by TCDD and BaP in human T47D-KBluc cells. We speculate that ERα is capable of interfereing AhR-medicated gene expression. Furtherr, we observed that AhR agonists were capable of modulating the expression of ERα-dependent progesterone receptor (PR). Down regulation of E2-mediated PR gene expression induced by TCDD was completely blocked by the addition of an AhR inhibitor, 3'',4''- dimethoxyflavone. In conclusions, we demonstrated that the (anti)-estrogenic effects of the model compounds selected in this study correlates with their respective AhR binding affinity and the mechanisms by which AhR agonists exert their action on ER-dependent gene expression in human T47D-KBluc breast cancer cells are likely mediated via AhR-ERα cross-talk.
其他識別: U0005-2907200911022200
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