【摘要】：第一部分母親妊娠前高雄出生子代隨訪、印跡基因表達及甲基化狀況目的:觀察母親妊娠前高雄出生子代的生長發(fā)育及幼年期血壓、血脂、血糖情況,研究子代糖代謝相關(guān)印記基因表達差異及甲基化改變,評估母親高雄對子代表型及表觀遺傳的影響。材料和方法:對2002-2008年在浙江大學(xué)醫(yī)學(xué)院附屬婦產(chǎn)科醫(yī)院診斷為高雄激素血癥并妊娠成功的患者進行隨訪,其子代作為實驗組,根據(jù)其妊娠方式(自然妊娠,促排卵后妊娠,IVF-ET后妊娠)進行匹配,以同期正常自然妊娠或因男性/管性因素經(jīng)促排卵或IVF-ET后出生子代為對照組,比較分析兩組子代圍產(chǎn)期情況,生長發(fā)育指標,血糖(空腹,口服糖耐量試驗OGTT)、血脂及血壓水平。利用熒光定量PCR檢測子代外周血糖代謝相關(guān)父/母源性印記基因表達,利用亞硫氫酸鹽測序的方法檢測差異表達基因差異甲基化區(qū)域(DMR)的甲基化水平。同時收集臨床廢棄人卵母細胞,體外高雄激素處理后采用免疫熒光檢測卵母細胞母源性印跡基因IGF2表達改變。結(jié)果:1.本研究共隨訪80名母親高雄出生子代及146名對照組子代,高雄子代出生體重、孕周、早產(chǎn)率較對照組均無顯著性差異;2.隨訪時兩組子代的年齡、體重指數(shù)(BMI)、血壓及血脂水平均無顯著性差異,母親高雄出生子代的空腹血糖(4.72±0.04mmol/L vs.4.60±0.03mmol/L,p0.05)、空腹胰島素(3.58±0.18μU/ml vs.3.12±0.15μU/ml,p0.05)及 HOMA 胰島素抵抗指數(shù)(0.76±0.04 vs.0.66±0.03,p0.05)均顯著高于對照組;3.其中74名高雄組子代及66 名對照組進行了 OGTT,兩小時血糖(5.12±0.13mmol/Lvs.4.85±0.15mmol/L,p0.05)及胰島素水平(10.53±2.03μU/mlvs.4.72±1.08μU/ml,p0.01)高雄子代均顯著高于對照子代;4.高雄子代外周血淋巴細胞母源性印記基因IGF2及GRB10的表達顯著增高,其相應(yīng)差異甲基化區(qū)顯著低甲基化;體外雄激素處理后,卵母細胞IGF2表達顯著升高。結(jié)論:母親妊娠前高雄出生子代幼年期空腹及糖耐量試驗中糖/胰島素水平均發(fā)生改變,但隨訪中未發(fā)現(xiàn)血糖/胰島素異常的子代;糖代謝相關(guān)印記基因IGF2及GRB20表達增高可能與高雄子代糖代謝水平改變有關(guān),甲基化水平降低為印記基因表達上調(diào)的機制,提示母親高雄影響子代表觀遺傳。第二部分妊娠前高雄大鼠子代表型、親代卵母細胞及子代胰島Igf2表達及甲基化檢測目的:研究妊娠前高雄大鼠子代的糖/胰島素代謝狀況,評估高雄致子代糖尿病的風(fēng)險;研究高雄對親代卵母細胞及子代胰島中印跡基因Igf2表達及甲基化水平的影響,明確表觀遺傳改變的傳代效應(yīng)。材料與方法:建立雌性高雄激素大鼠模型,交配前(6周齡)檢測血睪酮及游離雄激素指數(shù)。7周齡將高雄雌鼠與正常雄鼠交配得到高雄組子代,同齡正常雌鼠與正常雄鼠交配得到對照組子代。檢測兩組子代的出生體重、幼年期(3周齡)及成年期(8周齡)體重、日能量消耗及飲水量,血糖儀檢測空腹血糖并行糖耐量試驗,ELISA試劑盒檢測胰島素水平。分離純化大鼠子代胰島細胞和親代MII期卵母細胞,實時定量PCR檢測印記基因表達,亞硫酸氫鹽測檢測IGF2差異甲基化區(qū)甲基化狀態(tài)。結(jié)果:1.母親妊娠前高雄出生子代的出生體重于對照組相比無顯著性差異;2.高雄子代自幼年期出現(xiàn)日飲水量增多及日能量消耗增多,且這一表型一直持續(xù)至成年期;3.高雄子代空腹血糖顯著高于對照組,并且有27%在幼年期即出現(xiàn)糖尿病(GTT30min血糖11.1mmol/L)。發(fā)育至成年期,雖然高雄子代的空腹血糖與對照組相比無顯著性差異,但在GTT30min及60min時,其血糖水平仍顯著高于對照組,且76%的成年高雄子代仍表現(xiàn)出糖尿病;4.高雄子代幼年期空腹及注射葡萄糖后的胰島素水平均顯著低于對照組,成年期空腹胰島素與對照組無顯著性差異,然而注射葡萄糖后其胰島素水平仍顯著低于對照子代;5.高雄子代胰島細胞Igf2較對照組顯著高表達,且胎鼠胰島中Igf2DMR2甲基化水平顯著降低;6.高雄親代卵母細胞Igf2同樣高表達,Igf2DMR2甲基化水平也顯著低于對照組,更有趣的是,親代卵母細胞中3個低甲基化的CpG位點與子代胎胰島細胞的3個低甲基化CpG位點相對應(yīng)。結(jié)論:1.大鼠母親妊娠前高雄致子代糖尿病;2.妊娠前高雄出生子代胰島素釋放功能受損,是導(dǎo)致子代糖尿病的主要原因;3.高雄子代胰島印記基因Igf2表達異常,可能是其胰島細胞功能不良的機制之一;4.高雄子代胰島Igf2DMR2甲基化水平降低,為Igf2表達升高的機制;5.妊娠前高雄暴露致卵母細胞Igf2表達及甲基化水平改變,這種異常的表觀遺傳修飾可從親代卵母細胞(配子)傳遞至子代胰島細胞(體細胞),是母親高雄致子代糖代謝異常的主要機制之一。第三部分高雄激素對甲基轉(zhuǎn)移酶3a表達的調(diào)控目的:研究雄激素對甲基轉(zhuǎn)移酶3a(DNMT3a)表達的調(diào)控,從體內(nèi)及體外細胞培養(yǎng)兩個方面探討雄激素調(diào)節(jié)DNMT3a表達的分子機制。材料與方法:獲取高雄激素造模的大鼠MII卵母細胞,采用免疫熒光比較高雄狀態(tài)下的卵母細胞與正常卵母細胞DNMT3a表達的差異;體外實驗以人原代顆粒細胞及人KGN顆粒細胞為研究對象,通過不同濃度的雙氫睪酮(DHT)處理,以及雄激素受體(AR)小干擾RNA處理細胞后再加入不同濃度DHT處理,采用實時定量PCR及Western技術(shù)分別檢測顆粒細胞中DNMT3a mRNA和蛋白水平的表達改變;在KGN顆粒細胞系中應(yīng)用實時定量PCR及Western檢測不同濃度DHT對轉(zhuǎn)錄因子STAT3的調(diào)節(jié),并利用染色質(zhì)免疫共沉淀技術(shù),明確DNMT3a DNA上是否存在STAT3反應(yīng)元件,進一步確定其結(jié)合位點。結(jié)果:1.在體實驗顯示,高雄大鼠卵母細胞中DNMT3a與對照組相比顯著低表達;2.體外細胞實驗顯示,DHT可濃度依賴性的下調(diào)原代顆粒細胞DNMT3a mRNA,同時上調(diào)印記基因IGF2 mRNA;相應(yīng)地,DHT可在mRNA水平濃度依賴性的下調(diào)KGN細胞DNMT3a的表達;SiRNA敲減AR可阻斷DHT對DNMT3a的下調(diào)作用;3.DHT可濃度依賴性降低STAT3的表達;4.DNMT3a轉(zhuǎn)錄起始位點上游-1118bp處存在著STAT3的結(jié)合位點。結(jié)論:1.體內(nèi)高雄可降低大鼠卵母細胞甲基化建立關(guān)鍵酶DNMT3a的表達,這可能是高雄激素干擾卵母細胞母源性印記的建立過程,從而導(dǎo)致其印記基因IGF2甲基化水平降低、表達上調(diào)的重要機制;2.人顆粒細胞體外實驗顯示高雄激素從mRNA及蛋白水平下調(diào)DNMT3a的表達,且這一調(diào)控是通過雄激素受體通路來進行的;3.DNMT3a啟動子區(qū)存在轉(zhuǎn)錄因子STAT3的反應(yīng)元件,高濃度雄激素下調(diào)STAT3蛋白可能是其從mRNA 轉(zhuǎn)錄水平降低DNMT3a表達的機制之一。
[Abstract]:The first part of the mother's pregnancy, Kaohsiung birth subgeneration follow-up, imprinted gene expression and methylation status: Observation of the growth and development of the offspring of Kaohsiung before pregnancy, blood pressure, blood lipid, blood glucose, the difference of the expression of glycometabolism related gene expression and the change of methylation, and the evaluation of the representative and table of the mother of the mother Kaohsiung. Effects of epigenetic effects. Materials and methods: a follow-up of 2002-2008 years at the hospital of Obstetrics and Gynecology, affiliated to the Medical College of Zhejiang University, which was diagnosed as Kaohsiung hormone and pregnancy success, was followed up as an experimental group and matched according to the way of pregnancy (natural pregnancy, ovulatory pregnancy, IVF-ET pregnancy), in the same period of normal natural pregnancy or The perinatal period, growth and development index, blood glucose (fasting, oral glucose tolerance test OGTT), blood lipid and blood pressure level were compared and analyzed in two groups of subgeneration perinatal period, and blood glucose and blood pressure levels were compared between the two groups. The methylation level of differentially expressed genes in the methylation region (DMR) was detected by the acid salt sequencing method. At the same time, the clinical abandoned human oocytes were collected and the oocyte maternal maternal imprinted gene IGF2 expression was detected by immunofluorescence in Kaohsiung. The results were as follows: 1. studies were followed up by 80 mothers in Kaohsiung and 146 pairs. There was no significant difference in birth weight, pregnancy week and preterm birth rate in Kaohsiung subgeneration, and there was no significant difference in the age of the two groups, body mass index (BMI), blood pressure and blood lipid levels in the two groups, and the fasting insulin (4.72 + 0.04mmol/L vs.4.60 + 0.03mmol/L, P0.05) and fasting insulin (3.58 + 0.18 u U/ml) at the birth of the mother. Vs.3.12 + 0.15 U/ml, P0.05) and HOMA insulin resistance index (0.76 + 0.04 vs.0.66 + 0.03, P0.05) were significantly higher than those of the control group. 3. of the 74 Kaohsiung group and 66 control groups had OGTT, two hours blood glucose (5.12 + 0.13mmol/Lvs.4.85 + 0.15mmol/L, P0.05) and Isle level (10.53 + 2.03 mu U/mlvs.4.72 + 1.08 U/ml,) The male progeny was significantly higher than that of the control subgeneration; the expression of IGF2 and GRB10 in the peripheral blood lymphocyte imprinting genes of 4. Kaohsiung progeny increased significantly, and the corresponding differential methylation area was significantly lower methylation. After androgens treated in vitro, the expression of IGF2 in oocytes increased significantly. Conclusion: the fasting and glucose tolerance of the offspring of the parent of the parent of Kaohsiung before pregnancy. The glucose / insulin levels were all changed in the dose test, but the blood glucose / insulin abnormal progeny was not found in the follow-up. The increased expression of IGF2 and GRB20 may be related to the change of sugar metabolism in Kaohsiung substitutes. The reduction of methylation level is the mechanism of the up-regulation of the imprinted gene expression, which suggests that mother Kaohsiung influence the representation of the offspring. Second part of the representative type of Kaohsiung rats before pregnancy, the expression of Igf2 expression and methylation of the oocytes and offspring islets of the parents: To study the glucose / insulin metabolism in the rat of Kaohsiung before pregnancy, to evaluate the risk of diabetes in Kaohsiung, and to study the expression of Igf2 in the parent and offspring islets of the parent and the offspring of the offspring. The effect of epigenetic changes on the generation effect of epigenetic changes. Materials and methods: the female Kaohsiung hormone rat model was established. The blood testosterone and the free androgen index.7 weeks before mating (6 weeks old) were used to mate Kaohsiung female rats with the normal male rats, and the normal female rats of the same age were matched with the normal male rats to get the control group. The birth weight of two groups of offspring, young (3 weeks old) and adult (8 weeks old) body weight, daily energy consumption and drinking water were measured. Glucose meter detected fasting blood glucose and glucose tolerance test, ELISA kit detected insulin level. Isolated and purified rat subgeneration islet cells and parent MII oocytes, real-time quantitative PCR detection of imprinted gene expression, The methylation status of IGF2 differential methylation area was measured by hydrogen sulphite. Results: 1. the birth weight of Kaohsiung birth progeny before pregnancy was not significantly different from that of the control group; 2. Kaohsiung progeny had increased daily drinking water and increased daily energy consumption, and the phenotypes lasted to adulthood; 3. of the Kaohsiung offspring had fasting blood glucose. Significantly higher than the control group, and 27% of the onset of diabetes (GTT30min blood glucose 11.1mmol/L). Development to adulthood, although the fasting blood glucose of the Kaohsiung offspring had no significant difference compared with the control group, but at GTT30min and 60min, the blood glucose level was still significantly higher than that of the control group, and 76% of the adult progeny still showed diabetes; 4. The level of insulin after the infancy and the injection of glucose in the juvenile of Kaohsiung was significantly lower than that in the control group. There was no significant difference between the adult fasting insulin and the control group. However, the insulin level was still significantly lower than that of the control group after the injection of glucose; 5. the Igf2 of the Kaohsiung subgeneration islet cells was significantly higher than that of the control group, and the Igf2DMR in the pancreatic islets of fetal rats was significantly higher than that of the control group. The level of 2 methylation decreased significantly; 6. the Igf2 oocyte in Kaohsiung was also highly expressed, and the level of Igf2DMR2 methylation was also significantly lower than that of the control group. More interestingly, the 3 CpG loci in the parent oocyte were corresponding to the 3 hypomethylation CpG loci of the fetal islet cells. 2. the impaired insulin release in Kaohsiung before pregnancy was the main cause of subgeneration insulin release, which was the main cause of subgeneration diabetes; 3. the expression of islet imprinting gene Igf2 in the 3. progeny of Kaohsiung was one of the mechanisms of its islet cell dysfunction; 4. of the Kaohsiung subgeneration islet islet methylation water decreased, the mechanism of Igf2 expression increased, and 5. before pregnancy. The expression of Igf2 and the change of methylation level in male oocytes. This abnormal epigenetic modification can be transferred from parent oocytes (gametes) to progeny islet cells (somatic cells). It is one of the main mechanisms of abnormal glycometabolism in the offspring of mother Kaohsiung. The third part of the regulation of the expression of methyltransferase 3A by the hormone of the hormone of Kaohsiung: the study of male The regulation of hormone on the expression of methyltransferase 3A (DNMT3a) and the molecular mechanism of androgen regulation of DNMT3a expression from two aspects in vivo and in vitro culture. Materials and methods: to obtain MII oocytes from Kaohsiung hormone model rats, and to compare the difference between the expression of DNMT3a in oocyte and normal oocyte in Kaohsiung state by immunofluorescence In vitro, in vitro, human primary granulosa cells and human KGN granulosa cells were treated with different concentrations of dihydrotestosterone (DHT), and androgen receptor (AR) small interference RNA treated cells and then added to different concentrations of DHT treatment. Real-time quantitative PCR and Western techniques were used to detect DNMT3a mRNA and protein levels in granular cells respectively. Expression changes; in the KGN granular cell line, real-time quantitative PCR and Western were used to detect the regulation of DHT on the transcription factor STAT3, and chromatin immunoprecipitation technique was used to determine whether there was a STAT3 reaction element on DNMT3a DNA and further determine its binding site. Results: 1. in the body experiment, DNMT3 in the oocytes of Kaohsiung rats A was significantly lower than the control group; 2. in vitro cell experiments showed that DHT could downregulate DNMT3a mRNA in primary granulosa cells and increase the imprinting gene IGF2 mRNA; correspondingly, DHT could down regulate the expression of KGN cell DNMT3a in mRNA level, and SiRNA knockdown AR could block the downregulation effect of mRNA. Dependence reduces the expression of STAT3, and there is a binding site for STAT3 at the upstream -1118bp of the 4.DNMT3a transcription site. Conclusion: 1. in vivo Kaohsiung can reduce the expression of the key enzyme of the methylation of oocytes in rat oocytes, which may be the process of the establishment of the maternal imprint of the oocyte by Kaohsiung hormone, leading to the imprinting gene IGF2 a. In vitro experiments of 2. human granulosa cells showed that the expression of DNMT3a was down regulated from mRNA and protein levels in the 2. human granulosa cells, and this regulation was carried out through the androgen receptor pathway; the 3.DNMT3a promoter region has a reverse component of the transcription factor STAT3, and the high concentration of androgen regulation of the STAT3 protein may be It is one of the mechanisms to reduce DNMT3a expression from mRNA transcription level.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R714.2

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