得克隆通过ER介导的类雌激素作用研究

发布时间：2018-03-10 06:44

本文选题：得克隆　切入点：类雌激素效应　出处：《大连海事大学》2017年硕士论文　论文类型：学位论文

【摘要】：得克隆(Dechlorane Plus,DP)作为一种氯代阻燃剂,广泛地分布于环境和各类生物组织中,且容易在生殖腺内蓄积。本课题组前期研究表明,DP具有类雌激素效应,能导致人乳腺癌细胞MCF-7的增殖,并对雌激素受体(Estrogen Receptor,ER)及MAPK/ERK通路靶基因的表达产生影响,但其类雌激素效应的分子机制尚不清楚。本论文将主要对其类雌激素的分子机制进行研究。本论文分别采用ER阴性人乳腺癌细胞MDA-MB-231和ER阳性人乳腺癌细胞MCF-7进行DP体外(in vitro)暴露实验,首先明确DP的类雌激素作用是否依赖ER介导,并在此基础上,对ER介导的基因组和非基因组途径进行深入研究。结果表明,DP不能导致ER阴性人乳腺癌细胞MDA-MB-231的增殖,说明DP引起的类雌激素效应主要依赖ER介导。在基因组途径研究中,通过对细胞核内和膜上不同ER亚型的定量分析及转录激活实验,证明DP可引起核内的雌激素受体α(Estrogen Receptor α,ERα)表达上调,并与其同源二聚体结合,作用于靶基因上游启动子区域的雌激素反应元件(estrogen responsive element,ERE)上发挥类雌激素效应;但DP不能导致核内ERcα的磷酸化水平升高。非基因组途径的研究表明,DP通过激活MAPK/ERK通路中的级联分子发挥类雌激素作用。本论文的研究结果将为DP的生物毒性和生态危害评价提供理论依据。
[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 伪 strogen Receptor 伪 er 伪 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 伪 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.
【学位授予单位】：大连海事大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R114

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