發(fā)布時間：2018-04-16 14:29

  本文選題：DES + MEHP�。� 參考：《北京協(xié)和醫(yī)學(xué)院》2013年碩士論文

【摘要】：流行病學(xué)研究表明,在個體發(fā)育的窗口期暴露于內(nèi)分泌干擾物可以導(dǎo)致脂肪形成和肥胖發(fā)生。DES(己烯雌酚)是一種類雌激素物質(zhì),廣泛存在于化妝品和禽蛋中；DEHP(鄰苯二甲酸-2-乙基己基酯)是塑料制品工業(yè)中普遍使用的一種增塑劑,DEHP—旦被人體攝入便代謝為其單體形式MEHP(鄰苯二甲酸-單-2-乙基己基酯),而MEHP更易被人體吸收進而影響人體健康。DES或MEHP在食物鏈中蓄積并通過多種途徑進入人體,進而擾亂機體正常的內(nèi)分泌系統(tǒng)和代謝通路,破壞機體脂肪組織自穩(wěn)態(tài)的調(diào)節(jié),導(dǎo)致肥胖。然而,國內(nèi)外學(xué)術(shù)界對DES和MEHP致肥作用的研究開展相對較晚。動物實驗、人體實驗以及大量的流行病學(xué)統(tǒng)計非常缺乏。DES和MEHP誘導(dǎo)脂肪組織形成機制的研究為之甚少,其分子機制尚不明確。因此,我們分別從體內(nèi)和體外水平評估DES和MEHP在脂肪細(xì)胞分化中的作用,探索其潛在的作用機制。 在本研究中,油紅O染色和3-磷酸甘油脫氫酶(GPDH)活性分析的結(jié)果表明：DES可以在體外誘導(dǎo)3T3-L1前脂肪細(xì)胞分化成為成熟的脂肪細(xì)胞,具體表現(xiàn)為細(xì)胞內(nèi)脂滴聚集增多,3-磷酸甘油脫氫酶(GPDH)活性升高,并且是以劑量依賴的方式進行。DES在體外誘導(dǎo)脂肪細(xì)胞增殖分化的分子機制是通過細(xì)胞雌激素受體作用于細(xì)胞,通過調(diào)節(jié)PPARγ、促進與脂肪細(xì)胞分化、脂肪形成相關(guān)的基因的表達從而促進脂肪形成；體內(nèi)也遵循同樣的機制。圍產(chǎn)期宮內(nèi)暴露低劑量DES可以使成年(2個月)子代雌性小鼠的體重、肝重和脂肪墊重量顯著增加,而且甘油三酯和血糖水平也顯著升高。 油紅O染色結(jié)果顯示1-100μM MEHP可以誘導(dǎo)前脂肪細(xì)胞系3T3-L1分化為成熟的脂肪細(xì)胞,表現(xiàn)為細(xì)胞內(nèi)脂滴聚集增多,3-磷酸甘油脫氫酶(GPDH)活性升高；并且隨誘導(dǎo)濃度增加,細(xì)胞分化程度升高。分子水平檢測顯示,MEHP在誘導(dǎo)脂肪細(xì)胞分化過程中激活PPARy及其下游靶基因aP2和LPL的表達。進一步體內(nèi)證據(jù)表明,低劑量(0.05mg/kg體重)MEHP明顯誘導(dǎo)雄性子代小鼠成年后肥胖的發(fā)生,具體表現(xiàn)為：體重和體脂含量增加,血清總膽固醇、甘油三酯和血糖水平的異常上升。分子水平檢測表明,MEHP宮內(nèi)暴露激活體內(nèi)PPARy及其靶基因aP2, FAS和LPL的表達上調(diào),而對促進脂肪酸氧化的PPARa無誘導(dǎo)效應(yīng)。提示鄰苯二甲酸酯MEHP分別從體內(nèi)、外水平誘導(dǎo)脂肪細(xì)胞分化進而促進肥胖的發(fā)生。 綜上,我們的研究結(jié)果表明宮內(nèi)暴露于低劑量的DES或MEHP通過激活PPARy信號通路,進而誘導(dǎo)脂肪細(xì)胞分化,導(dǎo)致肥胖發(fā)生。因此,DES或MEHP可能作為潛在的化學(xué)誘導(dǎo)因子誘發(fā)肥胖及相關(guān)疾病發(fā)生。
[Abstract]:Epidemiological studies have shown that exposure to endocrine disruptors during the ontogeny window can lead to fat formation and obesity. DES (diethylstilbestrol) is an estrogen substance.DEHP- (phthalic acid-2-ethylhexyl ester) is a kind of plasticizer widely used in plastics industry, which is widely used in cosmetics and eggs. DEHP- (phthalic acid-mono-2-ethylhexyl) is metabolized by human body and then metabolized as its monomer form (phthalic acid-mono-2-ethylphthalate).Hexyl ester, and MEHP is more easily absorbed by the human body and then affects human health. Des or MEHP accumulates in the food chain and enters the human body through a variety of channels.Thus disrupting the normal endocrine system and metabolic pathway, disrupting the self-stable regulation of adipose tissue, resulting in obesity.However, the research on the effect of DES and MEHP on the effect of fertilization is relatively late in academic circles at home and abroad.Animal experiments, human experiments and a large number of epidemiological statistics lack of research on the mechanism of adipose tissue formation induced by .DES and MEHP, and its molecular mechanism is still unclear.Therefore, we evaluate the role of DES and MEHP in adipocyte differentiation in vivo and in vitro, and explore its potential mechanism.The results of oil red O staining and glycerol 3-phosphate dehydrogenase (GPDH) activity analysis showed that 3T3-L1 preadipocytes could differentiate into mature adipocytes in vitro.The results showed that the increase of lipid droplet aggregation in cells increased the activity of glycerol 3-phosphate dehydrogenase (GPDH), and the molecular mechanism of inducing adipocyte proliferation and differentiation in vitro by .DES in a dose-dependent manner was through the action of cellular estrogen receptor on the cells.By regulating PPAR 緯, the expression of genes related to adipocyte differentiation and adipogenesis is promoted, and the same mechanism is followed in vivo.Low dose DES exposure during perinatal period could significantly increase the body weight, liver weight and fat pad weight of adult (2 months) female mice, as well as the level of triglyceride and blood sugar.The results of oil red O staining showed that 1-100 渭 M MEHP could induce preadipose cell line 3T3-L1 to differentiate into mature adipocytes, and the activity of glycerol 3-phosphate dehydrogenase (GPDH) increased with the increase of lipid droplets.The degree of cell differentiation increased.Molecular level detection showed that MEHP activated the expression of PPARy and its downstream target genes aP2 and LPL during adipocyte differentiation.Further evidence in vivo showed that MEHP at a low dose of 0.05 mg / kg significantly induced obesity in male offspring after adulthood, as follows: the increase of body weight and body fat content, the abnormal increase of serum total cholesterol, triglyceride and blood glucose levels.Molecular level detection showed that the expression of PPARy and its target genes aP2, FAS and LPL were up-regulated by intrauterine exposure to MEHP, but not on PPARa, which promoted the oxidation of fatty acids.The results suggest that phthalate MEHP induces adipocyte differentiation in vivo and in vitro and promotes the development of obesity.In conclusion, our results suggest that intrauterine exposure to low-dose DES or MEHP induces adipocyte differentiation by activating the PPARy signaling pathway, leading to obesity.Therefore, des or MEHP may be a potential chemoinducer to induce obesity and related diseases.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R114

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