發(fā)布時(shí)間：2018-04-13 11:19

  本文選題：體外受精 + 動(dòng)態(tài)突變　； 參考：《浙江大學(xué)》2014年博士論文

【摘要】：第一部分輔助生殖技術(shù)對(duì)動(dòng)態(tài)突變頻率的影響 目的： 調(diào)查ART出生兒動(dòng)態(tài)突變的發(fā)生頻率及其改變幅度,比較其與自然妊娠出生兒之間的差異,探討ART對(duì)動(dòng)態(tài)突變基因三核苷酸重復(fù)拷貝數(shù)突變頻率和幅度的影響,為ART對(duì)DNA穩(wěn)定性的效應(yīng)研究提供證據(jù)。 材料和方法： 收集2008-2012年在浙江大學(xué)醫(yī)學(xué)院附屬婦產(chǎn)科醫(yī)院完成分娩的ART家系147例,其中包括75例IVF家系和72例ICSI家系。同時(shí)收集在該院完成分娩的99例自然妊娠家系,作為正常對(duì)照。采集新生兒的臍帶血和父母親的靜脈血,提取DNA。 以齒狀核紅核蒼白球丘腦下部核萎縮(dentatoubral and pallidoluysian atrophy, DRPLA),脊髓延髓肌萎縮(spinal and bular muscular atrophy,SBMA),脊髓小腦共濟(jì)失調(diào)Ⅰ型(spinocerebellar ataxia,SCA1),馬赫多-約瑟夫病(Machado-Joseph,MJD),亨廷頓病(Huntington's disease gene,HD),肌強(qiáng)直性肌萎縮(myotonic dystrophy,DM),脆性X綜合征(Fragile X syndrome,FraX)7種動(dòng)態(tài)突變疾病的致病基因：ATN1,AR,ATXN1,ATXN3,Huntington,DMPK,FMR-1基因?yàn)槟康幕颉?對(duì)所收集的246個(gè)家系(783個(gè)成員),PCR擴(kuò)增上述7個(gè)基因的三核苷酸重復(fù)序列區(qū),瓊脂糖凝膠電泳,8%非變性聚丙烯酰胺凝膠電泳、DNA的測(cè)序分析完成各家系各基因位點(diǎn)三核苷酸重復(fù)拷貝數(shù)檢測(cè),統(tǒng)計(jì)分析,比較各組間三核苷酸重復(fù)序列動(dòng)態(tài)突變頻率和拷貝數(shù)改變的幅度。結(jié)果： ART子代中共檢測(cè)2466個(gè)等位基因中,有52個(gè)等位基因發(fā)生突變,突變率為2.11%,與對(duì)照組子代突變率0.77%(10/1300)相比,差異具有統(tǒng)計(jì)學(xué)意義。其中IVF子代突變率為2.48%(32/1288),ICSI子代突變率為1.70%(20/1178),與對(duì)照組相比較,差異具有統(tǒng)計(jì)學(xué)意義,但是IVF與ICSI組之間無(wú)顯著性差異。在所有的這些被檢測(cè)家系中,各動(dòng)態(tài)突變位點(diǎn)的三核苷酸重復(fù)拷貝數(shù)既有增加,也有減少,但均在其正常范圍內(nèi)。 根據(jù)不孕不育背景,我們?cè)賹VF和ICSI再分成以下各小組：女性因素包括輸卵管性不孕,子宮內(nèi)膜異位癥,排卵障礙；男性因素包括少精,弱精,畸精及梗阻性無(wú)精子癥；男女雙方因素；不明原因不孕及其他因素。我們發(fā)現(xiàn)在ICSI組中,不孕因素為女方因素(3.90%)及男女雙方因素(2.59%)的發(fā)生動(dòng)態(tài)突變的頻率要高于單純男方因素(0.76%),差異具有統(tǒng)計(jì)學(xué)意義。 結(jié)論 1.ART子代動(dòng)態(tài)突變頻率高于自然妊娠子代。 2.ART技術(shù)及其不孕不育背景可能影響子代動(dòng)態(tài)突變頻率。 第二部分ART對(duì)子代胎盤(pán)DNA損傷修復(fù)基因的研究 目的： 研究ART子代胎盤(pán)組織中DNA損傷修復(fù)相關(guān)基因表達(dá),揭示ART子代基因組不穩(wěn)定性原因,并探索相關(guān)基因啟動(dòng)子區(qū)域DNA甲基化率改變與基因表達(dá)異常間的關(guān)系。 材料和方法： 收集2009年-2013年間在浙江大學(xué)醫(yī)學(xué)院附屬婦產(chǎn)科醫(yī)院剖宮產(chǎn)分娩的52例足月、單胎ART子代胎盤(pán)組織,其中包括32例常規(guī)IVF子代及20例ICSI子代。對(duì)照組為同期在我院剖宮產(chǎn)的32例自然妊娠子代。記錄母親年齡,出生體重,孕周等一般信息。 依據(jù)本論文第一部分結(jié)果顯示ART子代動(dòng)態(tài)突變頻率增高這一結(jié)果,選擇動(dòng)態(tài)突變相關(guān)DNA損傷修復(fù)基因?yàn)槟繕?biāo)基因：OGG1:8-oxoguanine DNA glycosylase; MSH6:mutS homolog6; MSH2:mutS homolog2; MSH3:mutS homolog3; MLH1: MutL homolog1; MLH3:MutL homolog3; PMS2:postmeiotic segregation increased2; PMS1:postmeiotic segregation increased1;XPA:xeroderma pigmentosum, complementation group A; APEXI:apurinic/apyrimidinic endonuclease1; RPA1: replication protein Al,選取胎盤(pán)為靶組織,進(jìn)行ART子代動(dòng)態(tài)突變不穩(wěn)定性的發(fā)生機(jī)制研究。 (1)ART子代胎盤(pán)中DNA損傷修復(fù)相關(guān)基因表達(dá)分析 利用熒光定量RT-PCR檢測(cè)ART子代胎盤(pán)中DNA損傷修復(fù)相關(guān)基因OGG1, MSH6, MSH2, MSH3, MLH1, MLH3, PMS2, PMS1,XPA, APEX1和RPA1的表達(dá)變化。 (2)ART子代胎盤(pán)中DNA損傷修復(fù)相關(guān)基因修飾分析 應(yīng)用焦磷酸測(cè)序技術(shù)檢測(cè)OGG1,RPA1,PMS2,MSH6和XPA這五個(gè)基因啟動(dòng)子區(qū)域甲基化狀態(tài)。 (3)ART子代胎盤(pán)中DNA損傷修復(fù)相關(guān)基因蛋白表達(dá)分析 通過(guò)western-blot檢測(cè)MLH1,OGG1,RPA1,PMS2,MSH2,MSH6和XPA各蛋白在胎盤(pán)組織的表達(dá)情況。 結(jié)果： (1) mRNA水平：IVF與ICSI組中,PMS2,RPA1,XPA,MSH2,MSH6基因相比較對(duì)照組存在高表達(dá),差異具有統(tǒng)計(jì)學(xué)意義。IVF組中的MLH1與對(duì)照組和ICSI組比較存在顯著性高表達(dá)；另外,與IVF組相比,ICSI組的MSH2,XPA,OGG1和RPA1基因也存在顯著性高表達(dá),差異具有統(tǒng)計(jì)學(xué)意義。 (2)DNA水平：OGG1,RPA1,PMS2,MSH6和XPA的CpG島的甲基化位點(diǎn)在IVF與ICSI組均與體內(nèi)組存在甲基化率的差異,并有統(tǒng)計(jì)學(xué)意義,與基因mRNA水平改變一致。 (3)蛋白水平：ICSI組的PMS2,MSH6和MLH1蛋白表達(dá)水平顯著高于IVF組及對(duì)照組,差異具有統(tǒng)計(jì)學(xué)意義。 結(jié)論： 1.ART操作及不孕不育背景可能子代胎盤(pán)組織DNA損傷修復(fù)相關(guān)基因的表達(dá)水平異常有關(guān)。 2.ART操作及不孕不育背景可能影響DNA損傷修復(fù)相關(guān)基因的DNA甲基化修飾。 3.DNA損傷修復(fù)相關(guān)基因的mRNA水平與蛋白水平不一致,可能與轉(zhuǎn)錄后調(diào)控有關(guān)。 第三部分ART對(duì)出生小鼠老年時(shí)期中樞神經(jīng)系統(tǒng)DNA氧化損傷及退行性改變的影響 目的： 研究ART出生小鼠在老年時(shí)期腦組織氧化損傷,DNA損傷修復(fù)基因及神經(jīng)退行性疾病相關(guān)基因,評(píng)估ART對(duì)出生小鼠老年時(shí)期中樞神經(jīng)系統(tǒng)DNA氧化損傷及退行性改變的影響。 材料和方法： 應(yīng)用已建好的ART老年C57BL/6J小鼠模型包括：8只IVF小鼠、8只ICSI小鼠、8只體內(nèi)受精小鼠(每組小鼠雌雄比率相似),選擇8-OHdG為DNA氧化損傷標(biāo)記物,選擇DNA損傷修復(fù)基因Msh2, Apex1,Msh6, Ogg1, Pcna, Xpa和Mlh1；神經(jīng)退行性疾病相關(guān)Mapt, Bacel,Psen1,Psen2, App, Apoe和相關(guān)microRNA以及Insulin/IGF-1信號(hào)通路有關(guān)基因?yàn)槟繕?biāo)基因。選取腦組織為靶組織,研究ART對(duì)出生小鼠老年時(shí)期中樞神經(jīng)系統(tǒng)DNA氧化損傷及退行性改變風(fēng)險(xiǎn)的影響。 (1)ART老年小鼠8-OHdG水平分析 利用ELISA檢測(cè)ART老年小鼠腦組織8-OHdG水平。 (2)ART老年DNA損傷修復(fù)相關(guān)基因表達(dá)分析 利用熒光定量RT-PCR檢測(cè)ART老年小鼠腦組織Msh2, Apex1,Msh6,Oggl, Pcna, Xpa和Mlhl的表達(dá)變化。 (3)ART老年神經(jīng)退行性疾病相關(guān)基因表達(dá)分析 利用熒光定量RT-PCR檢測(cè)ART老年小鼠腦組織Mapt, Bacel,Psen1,Psen2, App,Apoe,Igf-1,Igf-1r,Insr,Irs-1,Irs-2, miR-34與miR-101的表達(dá)變化。 (4)ART老年小鼠DNA損傷修復(fù)基因修飾分析 應(yīng)用焦磷酸測(cè)序技術(shù)檢測(cè)ART老年小鼠腦組織相關(guān)損傷修復(fù)基因的CpG島的甲基化狀態(tài)。 結(jié)果： (1)8-OHdG水平：對(duì)照組8-OHdG為4.26±1.54pg/ml, IVF組9.59±4.27pg/ml,ICSI組為8.57±3.90pg/ml,與體內(nèi)組相比,差異均具有統(tǒng)計(jì)學(xué)意義。但I(xiàn)VF與ICSI組之間無(wú)顯著性差異。 (2)DNA損傷修復(fù)相關(guān)基因mRNA水平：與體內(nèi)組相比,IVF和ICSI組的Ogg1, Apex1和Pcna基因表達(dá)顯著上調(diào)；IVF和ICSI組的Msh6,Msh2和Mlhl基因顯著性低表達(dá),差異均具有統(tǒng)計(jì)學(xué)意義。ICSI與IVF組相比,Pcna基因表達(dá)顯著上調(diào)。 (3)神經(jīng)退行性疾病相關(guān)基因mRNA和rmiRNA水平：與體內(nèi)組相比,ICSI組Psen1,Igf-1基因表達(dá)水平升高,Igf-1r,Insr,Irs-1, miR-34和miR-101表達(dá)水平下降,差異具有統(tǒng)計(jì)學(xué)意義；IVF組Igf-1基因表達(dá)水平升高,Igf-1r,Insr,Irs-1和miR-34表達(dá)水平下降,差異具有統(tǒng)計(jì)學(xué)意義。IVF與ICSI組相比,Insr和miR-101在ICSI組表達(dá)顯著性下降,差異具有統(tǒng)計(jì)學(xué)意義。 (4)DNA損傷修復(fù)相關(guān)基因DNA水平：Oggl和Mlhl的CpG島的甲基化位點(diǎn)在IVF與ICSI組均與體內(nèi)組存在甲基化率的差異,并有統(tǒng)計(jì)學(xué)意義。 結(jié)論：1.IVF/ICSI出生小鼠老年時(shí)期腦組織可能存在較高氧化損傷風(fēng)險(xiǎn)。2.IVF/ICSI出生小鼠老年時(shí)期可能存在較高中樞神經(jīng)系統(tǒng)退行性改變風(fēng)險(xiǎn),但進(jìn)一步機(jī)理尚需完善。
[Abstract]:The effect of assisted reproductive technology on the frequency of dynamic mutation in the first part
Objective:
Investigation of ART frequency and amplitude change was born with mutations in children compared with the dynamic difference between the natural pregnancy birth, to explore the influence of ART copy number mutation frequency and amplitude of dynamic mutation gene trinucleotide, provide evidence for the effect of ART on the stability of DNA.
Materials and methods:
Collected 2008-2012 years in women's Hospital School of medicine Zhejiang University completed the ART family delivery in 147 cases, including 75 cases of IVF families and 72 ICSI families were collected in the hospital. At the same time to complete the delivery of 99 cases of spontaneous pregnancy pedigrees, as normal control. The acquisition of neonatal umbilical cord blood and venous blood of the father mother extraction, DNA.
The dentatorubral pallidoluysian atrophy (dentatoubral and pallidoluysian atrophy, DRPLA), spinal bulbar muscular atrophy (spinal and BULAR muscular atrophy, SBMA), spinocerebellar ataxia type 1 (spinocerebellar ataxia SCA1), Magdo - Joseph's disease (Machado-Joseph, MJD), Huntington disease (Huntington's disease gene. HD), myotonic muscular atrophy (myotonic dystrophy, DM), fragile X syndrome (Fragile X, syndrome, FraX) gene 7 dynamic mutation disease: ATN1, AR, ATXN1, ATXN3, Huntington, DMPK, FMR-1 gene.
In 246 families collected (783 members), PCR amplified the 7 gene trinucleotide repeats, agarose gel electrophoresis, 8% non denaturing polyacrylamide gel electrophoresis, DNA sequencing analysis of complete families of the loci trinucleotide repeat copy number detection, statistics, comparisons between groups of trinucleotide repeat sequence dynamic mutation the frequency and amplitude of the copy number changes:
The ART offspring were detected 2466 alleles, 52 alleles mutation, the mutation rate was 2.11%, and the control group of offspring mutation rate was 0.77% (10/1300) compared to the difference was statistically significant. The IVF progeny mutation rate was 2.48% (32/1288), ICSI generation (the mutation rate was 1.70% 20/1178), compared with the control group, the difference was statistically significant, but no significant difference between IVF and ICSI group. In all these tested families, the dynamic mutation repeats has also decreased, but increased in the normal range.
According to the infertility background, then we will use IVF and ICSI of each group is divided into the following: female factors including tubal infertility, endometriosis, ovulation disorder; male factors including oligospermia, asthenospermia, abnormal sperm and obstructive azoospermia; both male and female factors; unexplained infertility and other factors. We found in ICSI in the group, for the woman's infertility factors (3.90%) and both factors (2.59%) the occurrence of dynamic mutation is higher than that of the pure male factors (0.76%), the difference was statistically significant.
conclusion
The frequency of dynamic mutation of the 1.ART progeny is higher than that of the natural pregnancy offspring.
The 2.ART technique and its infertility background may affect the frequency of the dynamic mutation of the offspring.
The study of the second part ART on the repair genes of DNA injury in the placenta of the offspring
Objective:
Objective to study the expression of DNA damage repair related genes in the placenta of ART offspring, reveal the cause of genomic instability in ART progeny, and explore the relationship between the alteration of DNA methylation rate and the abnormal expression of genes in promoter regions.
Materials and methods:
From 2009 -2013 years in 52 cases of term affiliated obstetrics and Gynecology Hospital of Zhejiang University School of medicine in cesarean delivery, fetal ART single offspring placenta tissue, including 32 cases of IVF and 20 cases of normal offspring ICSI offspring. The control group for the same period in our hospital 32 cases of cesarean section pregnancy offspring. Parent records Pro age, birth weight, gestational age and other general information.
On the basis of the first part of this paper shows that ART generation dynamic mutation frequency increased this result, dynamic mutation of DNA repair gene as target gene: OGG1:8-oxoguanine DNA glycosylase; MSH6:mutS homolog6; MSH2:mutS homolog2; MSH3:mutS homolog3; MLH1: MutL homolog1; MLH3:MutL homolog3; PMS2:postmeiotic segregation increased2; PMS1:postmeiotic segregation increased1; XPA:xeroderma pigmentosum, complementation group A APEXI:apurinic/apyrimidinic; endonuclease1; RPA1: replication protein Al, select the placenta as the target tissue, study on the mechanism of occurrence of instability mutation of ART progeny dynamic.
(1) analysis of gene expression related to DNA injury and repair in ART subplacental placenta
The expression changes of DNA damage repair related genes OGG1, MSH6, MSH2, MSH3, MLH1, MLH3, PMS2, PMS1, MLH3, and ART were detected by fluorescent quantitative RT-PCR.
(2) analysis of gene modification related to DNA injury and repair in ART subplacental placenta
The methylation status of the five gene promoter regions of OGG1, RPA1, PMS2, MSH6 and XPA was detected by pyrosequencing.
(3) analysis of gene protein expression related to DNA injury and repair in ART subplacental placenta
The expression of MLH1, OGG1, RPA1, PMS2, MSH2, MSH6 and XPA proteins in the placental tissue was detected by Western-blot.
Result:
(1): IVF and mRNA levels in group ICSI, PMS2, RPA1, XPA, MSH2, MSH6 gene has high expression compared with the control group, the difference was statistically significant.IVF in the MLH1 group compared with control group and ICSI group expressed significantly; in addition, compared with the IVF group, ICSI group, MSH2. XPA, OGG1 and RPA1 gene has high expression significantly, the difference was statistically significant.
(2) DNA level: the methylation sites of CpG island of OGG1, RPA1, PMS2, MSH6 and XPA in the IVF and ICSI groups are different from those in the body group, and the methylation rate is statistically significant, which is consistent with the change of gene mRNA level.
(3) protein level: the expression level of PMS2, MSH6 and MLH1 protein in ICSI group was significantly higher than that in the IVF group and the control group, and the difference was statistically significant.
Conclusion:
1.ART operation and infertility background may be related to the abnormal expression level of DNA damage repair related genes in the placenta tissue.
The 2.ART operation and the infertility background may affect the DNA methylation of DNA damage repair related genes.
The mRNA level of 3.DNA damage repair related genes is not consistent with the protein level, which may be related to post transcriptional regulation.
The effect of the third part ART on the oxidative damage and degenerative changes of DNA in the central nervous system of the aged mice
Objective:
Objective to study the oxidative damage, DNA damage repair genes and neurodegenerative diseases related genes in ART born mice in the elderly, and to evaluate the effect of ART on the oxidative damage and degenerative changes of DNA in the central nervous system of the aging mice.
Materials and methods:
Including the ART old C57BL/6J mouse model application has been built: 8 IVF mice and 8 ICSI mice, 8 mice (male and female mice in vivo fertilization rate, similar) 8-OHdG as markers of oxidative DNA damage, DNA damage repair genes Msh2, Apex1, Msh6, Ogg1, Pcna, Xpa and Mlh1; nerve degeneration disease related Mapt, Bacel, Psen1, Psen2, App, Apoe and microRNA and Insulin/IGF-1 pathway genes as target gene. Selection of brain tissue as the target tissue of ART on the impact of birth old age mouse central nervous system DNA oxidative damage and degenerative changes in risk.
(1) analysis of 8-OHdG level in ART aged mice
The level of 8-OHdG in brain tissue of ART aged mice was detected by ELISA.
(2) analysis of gene expression related to DNA injury and repair in ART
The changes in the expression of Msh2, Apex1, Msh6, Oggl, Pcna, Xpa and Mlhl in the brain tissues of ART aged mice were detected by fluorescence quantitative RT-PCR.
(3) analysis of gene expression related to senile neurodegenerative diseases in ART
The expression changes of Mapt, Bacel, Psen1, Psen2, App, Apoe, Igf-1, Igf-1r, Insr, Igf-1, Igf-1r, RT-PCR, ART in brain tissue of aged mice were detected by fluorescent quantitative RT-PCR.
(4) analysis of DNA damage repair gene modification in ART aged mice
The methylation status of CpG island in the brain tissue related damage repair gene of ART aged mice was detected by pyrosequencing.
Result:
(1) 8-OHdG level: 8-OHdG in the control group was 4.26 + 1.54pg/ml, IVF group was 9.59 + 4.27pg/ml, ICSI group was 8.57 + 3.90pg/ml, the difference was statistically significant compared with the in vivo group, but there was no significant difference between IVF and ICSI group.
(2) the level of DNA damage repair related gene mRNA: compared with group IVF and group ICSI in vivo, Ogg1, Apex1 and Pcna gene expression was significantly up-regulated in IVF and ICSI group; Msh6, low expression of Msh2 and Mlhl gene significantly, the differences were statistically significant.ICSI compared with IVF group, Pcna gene expression increased significantly.
(3) gene related neurodegenerative diseases, mRNA and rmiRNA levels: compared with the in vivo group, ICSI Psen1 group, the expression level of Igf-1 increased, Igf-1r, Insr, Irs-1, the expression level of miR-34 and miR-101 decreased, the difference was statistically significant; increasing the expression level of IVF Igf-1 gene Igf-1r, Insr, and Irs-1 levels miR-34 decreased, the difference was statistically significant.IVF compared with ICSI group, the expression of Insr and miR-101 in ICSI group was significantly decreased, the difference was statistically significant.
(4) DNA damage repair related gene DNA level: Oggl and Mlhl CpG island methylation sites in IVF and ICSI groups were different from the body group methylation rate, and had statistical significance.
Conclusion: there may be a high risk of oxidative damage in the brain tissue of 1.IVF/ICSI born mice in the old age. There may be a higher risk of central nervous system degenerative changes in.2.IVF/ICSI born mice in the old age, but the mechanism needs further improvement.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R714.8

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