本文選題：得克隆　切入點(diǎn)：類雌激素效應(yīng)　出處：《大連海事大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：得克隆(Dechlorane Plus,DP)作為一種氯代阻燃劑,廣泛地分布于環(huán)境和各類生物組織中,且容易在生殖腺內(nèi)蓄積。本課題組前期研究表明,DP具有類雌激素效應(yīng),能導(dǎo)致人乳腺癌細(xì)胞MCF-7的增殖,并對(duì)雌激素受體(Estrogen Receptor,ER)及MAPK/ERK通路靶基因的表達(dá)產(chǎn)生影響,但其類雌激素效應(yīng)的分子機(jī)制尚不清楚。本論文將主要對(duì)其類雌激素的分子機(jī)制進(jìn)行研究。本論文分別采用ER陰性人乳腺癌細(xì)胞MDA-MB-231和ER陽(yáng)性人乳腺癌細(xì)胞MCF-7進(jìn)行DP體外(in vitro)暴露實(shí)驗(yàn),首先明確DP的類雌激素作用是否依賴ER介導(dǎo),并在此基礎(chǔ)上,對(duì)ER介導(dǎo)的基因組和非基因組途徑進(jìn)行深入研究。結(jié)果表明,DP不能導(dǎo)致ER陰性人乳腺癌細(xì)胞MDA-MB-231的增殖,說(shuō)明DP引起的類雌激素效應(yīng)主要依賴ER介導(dǎo)。在基因組途徑研究中,通過(guò)對(duì)細(xì)胞核內(nèi)和膜上不同ER亞型的定量分析及轉(zhuǎn)錄激活實(shí)驗(yàn),證明DP可引起核內(nèi)的雌激素受體α(Estrogen Receptor α,ERα)表達(dá)上調(diào),并與其同源二聚體結(jié)合,作用于靶基因上游啟動(dòng)子區(qū)域的雌激素反應(yīng)元件(estrogen responsive element,ERE)上發(fā)揮類雌激素效應(yīng);但DP不能導(dǎo)致核內(nèi)ERcα的磷酸化水平升高。非基因組途徑的研究表明,DP通過(guò)激活MAPK/ERK通路中的級(jí)聯(lián)分子發(fā)揮類雌激素作用。本論文的研究結(jié)果將為DP的生物毒性和生態(tài)危害評(píng)價(jià)提供理論依據(jù)。
[Abstract]:As a chlorinated flame retardant, Dechlorane Plusp was widely distributed in the environment and various biological tissues, and was easily accumulated in the gonads. Our previous studies have shown that DDP has estrogenic effect and can lead to the proliferation of human breast cancer cells MCF-7. The expression of estrogen receptor Estrogen receptor ERand target gene of MAPK/ERK pathway was also affected. However, the molecular mechanism of its estrogen-like effect is not clear. In this thesis, the molecular mechanism of estrogen-like effect is mainly studied. In this thesis, ER negative human breast cancer cell MDA-MB-231 and ER positive human breast cancer cell MCF-7 were used to carry out the study. DP in Vitro exposure test, Firstly, it is clear whether the estrogen like action of DP depends on ER mediated, and on the basis of this, the genomic and non-genomic pathways mediated by ER are studied in depth. The results show that DDP can not induce the proliferation of MDA-MB-231 in ER negative human breast cancer cells. In the study of genome pathway, quantitative analysis and transcriptional activation of different ER subtypes in nucleus and on membrane were carried out. It was demonstrated that DP could up-regulate the expression of estrogen receptor 偽 strogen Receptor 偽 er 偽 in nucleus and bind to its homologous dimer, and play an estrogenic effect on the estrogen response element (estrogen responsive element ERE) in the upstream promoter region of the target gene. However, DP can not increase the phosphorylation level of ERc 偽 in nucleus. Studies on non-genomic pathway show that PDP acts as estrogen by activating cascade molecules in MAPK/ERK pathway. The results of this study will be the biotoxicity and biotoxicity of DP. State hazard assessment provides theoretical basis.
【學(xué)位授予單位】：大連海事大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R114

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