胰岛素对小鼠早期胚胎发育的程序化影响及相关分子机理的研究
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摘要
本研究利用糖尿病模型小鼠和胰岛素处理体外培养的2细胞胚胎至囊胚期,研究早期发育环境中的胰岛素对F1和F2代生长和胰岛功能的代谢程序化影响;通过检测印迹基因Igf2和H19在早期胚胎的表达和印迹控制区DNA甲基化的变化;采用基因表达谱芯片筛选相关的差异表达基因,以探讨胰岛素胎儿程序化作用的可能机理。
1.胰岛素对小鼠早期胚胎发育的程序化影响
1.1不同剂量STZ诱导糖尿病模型小鼠
通过一次性腹腔注射150 mg/kg b.w.和200 mg/kg b.w.的链脲菌素(STZ)以制作小鼠糖尿病模型;采用葡萄糖测定试纸和尿液分析试纸条联合检测模型小鼠血糖和尿糖的变化。注射STZ后第4周测定小鼠血清葡萄糖和胰岛素浓度,光镜观察胰岛的组织学改变,并使模型小鼠与正常雄鼠交配,观察交配和妊娠情况。结果表明:对照组血糖在观测期基本无变化,模型组血糖水平逐渐增加,三周后稳定。高剂量组血清葡萄糖浓度明显升高(P＜0.001),血清胰岛素水平极显著下降(P＜0.001);胰岛形态破坏严重;低剂量组小鼠血清葡萄糖分升高组和正常组,但血清胰岛素浓度均明显降低(P＜0.01),胰岛内可见炎性细胞浸润。血糖升高组小鼠交配能力下降,交配率仅为46.9%,流产率为73.9%,仔鼠出生死亡率为20%。结论:不同剂量的STZ均能诱发糖尿病,且影响雌鼠的交配能力和胚胎的生长发育。
1.2母体低胰岛素、高血糖环境对子代生长发育和胰岛功能的程序化影响
STZ诱导的糖尿病模型小鼠与正常雄鼠交配产下F1代,F1代雌鼠成年后,与正常雄鼠远交产下F2代,观察母体低胰岛素、高血糖环境对子代(F1和F2)生长发育和胰岛功能的程序化影响。结果显示:试验组F1代畸形率为9%,仔鼠出生重下降26.5%(P＜0.01)。F1代试验组血清葡萄糖浓度比对照组升高24.7%(P＜0.05),血清胰岛素浓度比对照组下降26%(P＜0.05)。F2代试验组血清葡萄糖浓度与对照组没有差异,但血清胰岛素浓度比对照组下降14.3%(P＜0.05)。F1代、F2代成年鼠胰岛素耐量损伤,产生胰岛素抵抗,胰岛凋亡细胞比例升高。提示:糖尿病母体环境影响子代胚胎发育和成年后产生胰岛素抵抗,这种影响可以传递至F2代。
1.3植入前胚胎胰岛素处理对子代生长发育和胰岛功能的程序化影响
将小鼠2细胞胚胎培养于KSOM+0.25μg/ml Insulin的培养液中,发育至囊胚后转移到假孕母鼠子宫。产下的雌鼠成年后(6周龄),与正常雄鼠远交产下F1代,观察暴露于高胰岛素环境的早期胚胎及其子代生长发育和胰岛功能的程序化影响。结果显示:试验组囊胚发育率升高16.4%(P＜0.05),仔鼠出生重升高17.8%(P＜0.05)。试验组成年小鼠血清葡萄糖和胰岛素浓度与对照组均无明显差异,但胰腺凋亡细胞明显增多,并显示口服葡萄糖和胰岛素耐量损伤;F1代试验组血清胰岛素浓度比对照组下降14.3%(P＜0.05),胰岛素耐量损伤,产生胰岛素抵抗。提示:胰岛素能促进早期胚胎生长,但会造成成年以及F1代小鼠胰岛素抵抗。
2.胰岛素胎儿程序化作用的机理
2.1母体低胰岛素、高血糖环境对早期胚胎印迹基因Igf2和H19表达和甲基化的影响
取糖尿病模型母鼠14天胎龄的胚胎,提取全胚胎的总RNA和DNA,检测印迹基因Igf2和H19的表达和印迹控制区(ICR)的甲基化状态。结果显示:试验组14天胚胎中Igf2 mRNA表达的相对丰度比对照组下降15.4%(P＜0.05),Real-time RT-PCR显示Igf2mRNA表达是对照组的0.65倍(P＜0.05),而H19 mRNA表达与对照组无差异。试验组Igf/H19印迹控制区的CpG甲基化率比对照组升高19.1%(P＞0.05)。提示:母体低胰岛素、高血糖环境影响早期胎儿印迹基因Igf2/H19印迹控制区CpG甲基化率,引起Igf2 mRNA表达的改变。
2.2植入前胚胎胰岛素处理对小鼠胚胎印迹基因Igf2/H19表达和甲基化的影响
将小鼠2细胞胚胎培养于KSOM+0.25μg/ml Insulin的培养基内,发育至桑椹胚和囊胚,囊胚转移到假孕母鼠子宫。提取桑椹胚、囊胚和14天胚胎的总RNA和总DNA,检测印迹基因Igf2和H19的表达和印迹控制区(ICR)的甲基化状态。Real-timeRT-PCR分析表明,试验组桑椹胚Igf2 mRNA表达是对照组的4.7倍,H19表达是对照组的5.7倍;试验组囊胚Igf2 mRNA表达是对照组的1.8倍,H19表达量是对照组的2.3倍;14天胚胎,试验组Igf2和H19 mRNA表达均是对照组的1.5倍(P＜0.05)。BSP测序法分析Igf2/H19印迹控制区的甲基化水平发现,试验组桑椹胚、囊胚和14天胚胎甲基化率分别为7.3%,32.3%和46%,分别比对照组下降86.4%,35.4%和19.2%(P＜0.01)。提示:植入前胚胎暴露于胰岛素可降低Igf2/H19印迹控制区DNA甲基化的水平,从而使Igf2和H19基因表达升高。
3.基因表达谱芯片筛选与胎儿程序化作用相关的差异表达基因
取糖尿病模型小鼠和对照组小鼠14胎龄的胚胎,提取胚胎的总RNA。逆转录成cDNA,将Cy3和Cy5 2种荧光分别标记到试验组和对照组的cDNA上,并与包含24859个基因的表达谱芯片进行杂交及扫描,重复3次实验,采用Agilent扫描仪进行扫描分析,软件读取数据,结果筛选出差异表达基因397个,其中有328个基因在试验组表达量比对照组大2倍,69个基因在试验组表达量比对照组小2倍,其中糖尿病相关基因Rrad(Ras-Related Associated with Diabetes)和Rasl12上调,该基因与Ⅱ型糖尿病胰岛素抵抗有关;Otx2 and Robo3基因下调,其主要调节脑和神经系统发育及脑细胞分化。提示:母体糖尿病环境影响早期胎儿基因表达,进而影响胚胎发育。
The objectives of the present study were(1) to reveal whether an altered intrauterine endocrine milieu in diabetic mice model in vivo and preimplantation embryos exposed to insulin in vitro would cause long term alterations in growth and development,as well as insulin secretion and action later in adult life;(2) to demonstrate the possible trans-generational effect by examining the alterations in growth and insulin secretion and function in F1 and F2 offspring,and(3) to elucidate whether this action involves epigenetic modification of imprinted genes via changes in DNA methylation.In addtion, DNA microarray was employed to identify the differentially expressed genes in fetuses from control and diabetic mice.
1.Effect of insulin on the metabolic programming of mouse embryonic development
1.1 Establishment of diabetic mouse model by streptozotocin injection in different doses
To establish type 1 diabetes mellitus(T1DM),mice were received intraperitoneal injection of streptozotocin(STZ) at the doses of 150mg/kg b.w.and 200mg/kg b.w.. Blood and urine glucose levels were detected by glucose and urine analyzing papers respectively.Pancreatic histological changes of islets were observed under light microscope.Serum insulin concentration was detected by radioimmunoassay.The female diabetic mice were mated to the normal male mice,the mating ability and fetal mortality were observed.The glucose concentration in the control group did not show alteration across the investigation period,while that of the STZ group was increasing with the time, reaching stabilized level 3 weeks after STZ injection.Significantly increased(P＜0.001) serum glucose concentration associated with significantly decreased(P＜0.001) serum insulin levels were observed in the high STZ dose group,with obviously impaired pancreatic isletβcells.In the low STZ dose group,serum insulin concentration was decreased(P＜0.01),while serum glucose level increased or unaltered.In increased glucose group(Glucose＞18mmol/L),the success mating rate,abortion rate and fetal mortality were 46.9%,73.9%and 20%,respectively.The results indicate that STZ can induce diabetes mellitus,and affect the female success mating rate and fetal development.
1.2 Effect of maternal low insulin and high glucose environment on programming of fetal development and pancreatic islet function
STZ-induced diabetic mice were mated to the normal male mice to produce F1 offspring.The adult female F1 mice were bred to give birth to F2 offspring.The alteration of fetal development and pancreatic islet function were observed to reveal the maternal effect.The F1 offspring from diabetic mice exhibited malformation rate of 9%, and 26.5%lower birth weight compared with the control group(P＜0.01).The serum glucose concentration was 24.7%higher(P＜0.05),while the serum insulin concentration was 26%lower than that of the control(P＜0.05).The F2 offspring did not show significant alterations in serum glucose level,but the concentration of serum insulin was 14.3%lower than that of the control(P＜0.05).Adult offspring of both F1 and F2 from diabetic mice displayed insulin resistance and higher apoptotic ratio in pancreas.The result demonstrate that altered maternal endocrine and metabolic status(low insulin and high glucose) could exert trans-generational effect on growth and development,as well as insulin secretion and function in F1 and F2 offspring.
1.3 Exposure of Mouse Preimplantation Embryos to Insulin influences fetus development and pancreatic islet programming
2-cell embryos were cultured in either 0 or 0.25μg/ml insulin to the blastocyst stage and then transferred into pseudo-pregnant recipient mice.The newboms were raised until sexual maturity and were bred with normal males to produce F1 offspring.The ratio of blastocyst in insulin-exposed group is 16.4%higher than that of the control(P＜0.05), and the birth weight of insulin-exposed group was 17.8%higher than that of the control group(P＜0.05).The differences of serum glucose and insulin between insulin-exposed and control group were not significant,but the treated group demonstrated higher apoptotic ratio in pancreas and insulin resistance in adulthood.The concentration of serum insulin in F1 of treated group was 14.3%lower than that of the control(P＜0.05) with insulin resistance in adulthood.The results indicate that insulin can stimulate early-embryo development and induce alterations in pancreas function,with lasting consequences of insulin tolerance in the offspring in adult life.
2.Mechanisms involved in the effect of early insulin intervention
2.1 Alterations in the expression and methylation levels of imprinted genes H19 and Igf2 of fetuses from Streptozotocin-Induced Diabetic mice
The mRNA expression and methylation levels of the growth-related imprinted genes, H19 and Igf2 in fetuses of Streptozotocin-Induced Diabetic mice were analyzed.Total RNA and DNA of E14 fetuses were extracted.The relative abundance of Igf2 mRNA in STZ treated group was decreased by 15.4%(P＜0.05).Real-time reverse transcription-polymerase chain reaction analysis revealed that the mRNA expression of Igf2 in fetuses from diabetic mice was 0.65-fold of the control counterparts,which is associated with 19.1%higher methylation ratio of all CpGs in the targeted region of genomic DNA.The results indicate that maternal diabetes would affect fetal development via altering the expression of impriting genes.The modified genomic DNA methylation status of imprinting genes may account for the change of gene expression.
2.2 Exposure of Mouse Preimplantation Embryos to Insulin Alters the Methylation Status of Imprinted Genes H19 and Igf2
2-cell embryos were cultured in either 0 or 0.25μg/ml insulin to the morula and blastocyst stage,and then transferred into pseudo-pregnant recipient mice.The DNA and RNA of morula,blastocyst and E14 fetuses were extracted to reveal the alterations of expression and methylation levels of the growth-related imprinted genes,H19 and Igf2. Real-time reverse transcription-polymerase chain reaction analysis revealed that the mRNA expression of Igf2 and H19 in insulin-exposed morula was 4.9 and 5.7 fold of control counterparts,in insulin-exposed blastocyst,that was 1.8 and 2.3-fold respectively. In the insulin-exposed fetuses,both of the mRNA expression of Igf2 and H19 were 1.5 fold of the control group(P＜0.05).The methylation ratio of all CpGs in the targeted region of genomic DNA increased by 86.4%,35.4%and 19.2%in the insulin-exposed morula,blastocyst and E14 fetuses,respectively compared with the control counterparts (P＜0.05).The results indicate that insulin exposure during the preimplantation stage modifies the genomic DNA methylation status of imprinted genes,alters the expression and affects fetal development.
3.Identification of differentially expressed genes in fetuses from control and diabetic mice using DNA microarray
Total RNA of E14 diabetic fetuses were extracted and cDNA were reverse transcribed.Cy3 and Cy5 fluorescent dyes were labeled to diabetic and control cDNA respectively,and used to hybridize mouse oligo-array containing 24,859 genes.Data were analyzed by using Agilent microarray scanner system.A total of 397 genes were found to be differentially expressed between the fetuses of diabetic and control mice.328 genes showed a more than 2-fold increase in the expression compared with the control, while 69 genes showed a more than 2-fold down regulation.For example,Otx2 and Robo3,proteins that are involved in cell differentiation,nervous system and brain development,are down-regulated in the fetuses of the diabetic mice.Ras112 and Rrad, that are associated with diabetes,are up-regulated in the fetuses of the diabetic mice.The present study indicate diabetes mellitus can induce differentially expressed genes,and affect fetal development.
1.胰岛素对小鼠早期胚胎发育的程序化影响
1.1不同剂量STZ诱导糖尿病模型小鼠
通过一次性腹腔注射150 mg/kg b.w.和200 mg/kg b.w.的链脲菌素(STZ)以制作小鼠糖尿病模型;采用葡萄糖测定试纸和尿液分析试纸条联合检测模型小鼠血糖和尿糖的变化。注射STZ后第4周测定小鼠血清葡萄糖和胰岛素浓度,光镜观察胰岛的组织学改变,并使模型小鼠与正常雄鼠交配,观察交配和妊娠情况。结果表明:对照组血糖在观测期基本无变化,模型组血糖水平逐渐增加,三周后稳定。高剂量组血清葡萄糖浓度明显升高(P＜0.001),血清胰岛素水平极显著下降(P＜0.001);胰岛形态破坏严重;低剂量组小鼠血清葡萄糖分升高组和正常组,但血清胰岛素浓度均明显降低(P＜0.01),胰岛内可见炎性细胞浸润。血糖升高组小鼠交配能力下降,交配率仅为46.9%,流产率为73.9%,仔鼠出生死亡率为20%。结论:不同剂量的STZ均能诱发糖尿病,且影响雌鼠的交配能力和胚胎的生长发育。
1.2母体低胰岛素、高血糖环境对子代生长发育和胰岛功能的程序化影响
STZ诱导的糖尿病模型小鼠与正常雄鼠交配产下F1代,F1代雌鼠成年后,与正常雄鼠远交产下F2代,观察母体低胰岛素、高血糖环境对子代(F1和F2)生长发育和胰岛功能的程序化影响。结果显示:试验组F1代畸形率为9%,仔鼠出生重下降26.5%(P＜0.01)。F1代试验组血清葡萄糖浓度比对照组升高24.7%(P＜0.05),血清胰岛素浓度比对照组下降26%(P＜0.05)。F2代试验组血清葡萄糖浓度与对照组没有差异,但血清胰岛素浓度比对照组下降14.3%(P＜0.05)。F1代、F2代成年鼠胰岛素耐量损伤,产生胰岛素抵抗,胰岛凋亡细胞比例升高。提示:糖尿病母体环境影响子代胚胎发育和成年后产生胰岛素抵抗,这种影响可以传递至F2代。
1.3植入前胚胎胰岛素处理对子代生长发育和胰岛功能的程序化影响
将小鼠2细胞胚胎培养于KSOM+0.25μg/ml Insulin的培养液中,发育至囊胚后转移到假孕母鼠子宫。产下的雌鼠成年后(6周龄),与正常雄鼠远交产下F1代,观察暴露于高胰岛素环境的早期胚胎及其子代生长发育和胰岛功能的程序化影响。结果显示:试验组囊胚发育率升高16.4%(P＜0.05),仔鼠出生重升高17.8%(P＜0.05)。试验组成年小鼠血清葡萄糖和胰岛素浓度与对照组均无明显差异,但胰腺凋亡细胞明显增多,并显示口服葡萄糖和胰岛素耐量损伤;F1代试验组血清胰岛素浓度比对照组下降14.3%(P＜0.05),胰岛素耐量损伤,产生胰岛素抵抗。提示:胰岛素能促进早期胚胎生长,但会造成成年以及F1代小鼠胰岛素抵抗。
2.胰岛素胎儿程序化作用的机理
2.1母体低胰岛素、高血糖环境对早期胚胎印迹基因Igf2和H19表达和甲基化的影响
取糖尿病模型母鼠14天胎龄的胚胎,提取全胚胎的总RNA和DNA,检测印迹基因Igf2和H19的表达和印迹控制区(ICR)的甲基化状态。结果显示:试验组14天胚胎中Igf2 mRNA表达的相对丰度比对照组下降15.4%(P＜0.05),Real-time RT-PCR显示Igf2mRNA表达是对照组的0.65倍(P＜0.05),而H19 mRNA表达与对照组无差异。试验组Igf/H19印迹控制区的CpG甲基化率比对照组升高19.1%(P＞0.05)。提示:母体低胰岛素、高血糖环境影响早期胎儿印迹基因Igf2/H19印迹控制区CpG甲基化率,引起Igf2 mRNA表达的改变。
2.2植入前胚胎胰岛素处理对小鼠胚胎印迹基因Igf2/H19表达和甲基化的影响
将小鼠2细胞胚胎培养于KSOM+0.25μg/ml Insulin的培养基内,发育至桑椹胚和囊胚,囊胚转移到假孕母鼠子宫。提取桑椹胚、囊胚和14天胚胎的总RNA和总DNA,检测印迹基因Igf2和H19的表达和印迹控制区(ICR)的甲基化状态。Real-timeRT-PCR分析表明,试验组桑椹胚Igf2 mRNA表达是对照组的4.7倍,H19表达是对照组的5.7倍;试验组囊胚Igf2 mRNA表达是对照组的1.8倍,H19表达量是对照组的2.3倍;14天胚胎,试验组Igf2和H19 mRNA表达均是对照组的1.5倍(P＜0.05)。BSP测序法分析Igf2/H19印迹控制区的甲基化水平发现,试验组桑椹胚、囊胚和14天胚胎甲基化率分别为7.3%,32.3%和46%,分别比对照组下降86.4%,35.4%和19.2%(P＜0.01)。提示:植入前胚胎暴露于胰岛素可降低Igf2/H19印迹控制区DNA甲基化的水平,从而使Igf2和H19基因表达升高。
3.基因表达谱芯片筛选与胎儿程序化作用相关的差异表达基因
取糖尿病模型小鼠和对照组小鼠14胎龄的胚胎,提取胚胎的总RNA。逆转录成cDNA,将Cy3和Cy5 2种荧光分别标记到试验组和对照组的cDNA上,并与包含24859个基因的表达谱芯片进行杂交及扫描,重复3次实验,采用Agilent扫描仪进行扫描分析,软件读取数据,结果筛选出差异表达基因397个,其中有328个基因在试验组表达量比对照组大2倍,69个基因在试验组表达量比对照组小2倍,其中糖尿病相关基因Rrad(Ras-Related Associated with Diabetes)和Rasl12上调,该基因与Ⅱ型糖尿病胰岛素抵抗有关;Otx2 and Robo3基因下调,其主要调节脑和神经系统发育及脑细胞分化。提示:母体糖尿病环境影响早期胎儿基因表达,进而影响胚胎发育。
The objectives of the present study were(1) to reveal whether an altered intrauterine endocrine milieu in diabetic mice model in vivo and preimplantation embryos exposed to insulin in vitro would cause long term alterations in growth and development,as well as insulin secretion and action later in adult life;(2) to demonstrate the possible trans-generational effect by examining the alterations in growth and insulin secretion and function in F1 and F2 offspring,and(3) to elucidate whether this action involves epigenetic modification of imprinted genes via changes in DNA methylation.In addtion, DNA microarray was employed to identify the differentially expressed genes in fetuses from control and diabetic mice.
1.Effect of insulin on the metabolic programming of mouse embryonic development
1.1 Establishment of diabetic mouse model by streptozotocin injection in different doses
To establish type 1 diabetes mellitus(T1DM),mice were received intraperitoneal injection of streptozotocin(STZ) at the doses of 150mg/kg b.w.and 200mg/kg b.w.. Blood and urine glucose levels were detected by glucose and urine analyzing papers respectively.Pancreatic histological changes of islets were observed under light microscope.Serum insulin concentration was detected by radioimmunoassay.The female diabetic mice were mated to the normal male mice,the mating ability and fetal mortality were observed.The glucose concentration in the control group did not show alteration across the investigation period,while that of the STZ group was increasing with the time, reaching stabilized level 3 weeks after STZ injection.Significantly increased(P＜0.001) serum glucose concentration associated with significantly decreased(P＜0.001) serum insulin levels were observed in the high STZ dose group,with obviously impaired pancreatic isletβcells.In the low STZ dose group,serum insulin concentration was decreased(P＜0.01),while serum glucose level increased or unaltered.In increased glucose group(Glucose＞18mmol/L),the success mating rate,abortion rate and fetal mortality were 46.9%,73.9%and 20%,respectively.The results indicate that STZ can induce diabetes mellitus,and affect the female success mating rate and fetal development.
1.2 Effect of maternal low insulin and high glucose environment on programming of fetal development and pancreatic islet function
STZ-induced diabetic mice were mated to the normal male mice to produce F1 offspring.The adult female F1 mice were bred to give birth to F2 offspring.The alteration of fetal development and pancreatic islet function were observed to reveal the maternal effect.The F1 offspring from diabetic mice exhibited malformation rate of 9%, and 26.5%lower birth weight compared with the control group(P＜0.01).The serum glucose concentration was 24.7%higher(P＜0.05),while the serum insulin concentration was 26%lower than that of the control(P＜0.05).The F2 offspring did not show significant alterations in serum glucose level,but the concentration of serum insulin was 14.3%lower than that of the control(P＜0.05).Adult offspring of both F1 and F2 from diabetic mice displayed insulin resistance and higher apoptotic ratio in pancreas.The result demonstrate that altered maternal endocrine and metabolic status(low insulin and high glucose) could exert trans-generational effect on growth and development,as well as insulin secretion and function in F1 and F2 offspring.
1.3 Exposure of Mouse Preimplantation Embryos to Insulin influences fetus development and pancreatic islet programming
2-cell embryos were cultured in either 0 or 0.25μg/ml insulin to the blastocyst stage and then transferred into pseudo-pregnant recipient mice.The newboms were raised until sexual maturity and were bred with normal males to produce F1 offspring.The ratio of blastocyst in insulin-exposed group is 16.4%higher than that of the control(P＜0.05), and the birth weight of insulin-exposed group was 17.8%higher than that of the control group(P＜0.05).The differences of serum glucose and insulin between insulin-exposed and control group were not significant,but the treated group demonstrated higher apoptotic ratio in pancreas and insulin resistance in adulthood.The concentration of serum insulin in F1 of treated group was 14.3%lower than that of the control(P＜0.05) with insulin resistance in adulthood.The results indicate that insulin can stimulate early-embryo development and induce alterations in pancreas function,with lasting consequences of insulin tolerance in the offspring in adult life.
2.Mechanisms involved in the effect of early insulin intervention
2.1 Alterations in the expression and methylation levels of imprinted genes H19 and Igf2 of fetuses from Streptozotocin-Induced Diabetic mice
The mRNA expression and methylation levels of the growth-related imprinted genes, H19 and Igf2 in fetuses of Streptozotocin-Induced Diabetic mice were analyzed.Total RNA and DNA of E14 fetuses were extracted.The relative abundance of Igf2 mRNA in STZ treated group was decreased by 15.4%(P＜0.05).Real-time reverse transcription-polymerase chain reaction analysis revealed that the mRNA expression of Igf2 in fetuses from diabetic mice was 0.65-fold of the control counterparts,which is associated with 19.1%higher methylation ratio of all CpGs in the targeted region of genomic DNA.The results indicate that maternal diabetes would affect fetal development via altering the expression of impriting genes.The modified genomic DNA methylation status of imprinting genes may account for the change of gene expression.
2.2 Exposure of Mouse Preimplantation Embryos to Insulin Alters the Methylation Status of Imprinted Genes H19 and Igf2
2-cell embryos were cultured in either 0 or 0.25μg/ml insulin to the morula and blastocyst stage,and then transferred into pseudo-pregnant recipient mice.The DNA and RNA of morula,blastocyst and E14 fetuses were extracted to reveal the alterations of expression and methylation levels of the growth-related imprinted genes,H19 and Igf2. Real-time reverse transcription-polymerase chain reaction analysis revealed that the mRNA expression of Igf2 and H19 in insulin-exposed morula was 4.9 and 5.7 fold of control counterparts,in insulin-exposed blastocyst,that was 1.8 and 2.3-fold respectively. In the insulin-exposed fetuses,both of the mRNA expression of Igf2 and H19 were 1.5 fold of the control group(P＜0.05).The methylation ratio of all CpGs in the targeted region of genomic DNA increased by 86.4%,35.4%and 19.2%in the insulin-exposed morula,blastocyst and E14 fetuses,respectively compared with the control counterparts (P＜0.05).The results indicate that insulin exposure during the preimplantation stage modifies the genomic DNA methylation status of imprinted genes,alters the expression and affects fetal development.
3.Identification of differentially expressed genes in fetuses from control and diabetic mice using DNA microarray
Total RNA of E14 diabetic fetuses were extracted and cDNA were reverse transcribed.Cy3 and Cy5 fluorescent dyes were labeled to diabetic and control cDNA respectively,and used to hybridize mouse oligo-array containing 24,859 genes.Data were analyzed by using Agilent microarray scanner system.A total of 397 genes were found to be differentially expressed between the fetuses of diabetic and control mice.328 genes showed a more than 2-fold increase in the expression compared with the control, while 69 genes showed a more than 2-fold down regulation.For example,Otx2 and Robo3,proteins that are involved in cell differentiation,nervous system and brain development,are down-regulated in the fetuses of the diabetic mice.Ras112 and Rrad, that are associated with diabetes,are up-regulated in the fetuses of the diabetic mice.The present study indicate diabetes mellitus can induce differentially expressed genes,and affect fetal development.
引文
1. Lucas A. Programming by early nutrition: an experimental approach[J]. J Nutr, 1998, 128 (2 Suppl): 401-406
2. Plagemann A, Harder T, Franke K, Kohlhoff R. Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers[J]. Diabetes Care, 2002,25(1): 16-22
3. Reusens B, Remacle C. Programming of the endocrine pancreas by the early nutritional environment[J]. Int Biochem Cell B, 2006, 38(5-6): 913-922
4. Martin-Gronert M S, Ozanne S E. Programming of appetite and type 2 diabetes[J]. Early Hum Dev, 2005, 81(12): 981-988
5. Fernandez-Twinn D S, Ozanne S E. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome[J]. Physiol Behav, 2006, 88(3): 234-243
6. Ravelli A C, van der Meulen J H, Michels R P, Osmond C, Barker D J, Hales C N, Bleker O P. Glucose tolerance in adults after prenatal exposure to famine[J]. Lancet, 1998, 351(9097): 173-177
7. Barker D J, Hales C N, Fall C H, Osmond C, Phipps K, Clark P M. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia, 1993,36(1 ):62-67
8. Bennett F, Watson-Brown C, Thame M, Wilks R, Osmond C, Hales N, Barker D, Forrester T. Shortness at birth is associated with insulin resistance in pre-pubertal Jamaican children[J]. Eur J Clin Nutr, 2002, 56(6): 506-511
9. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J]. Diabet Med, 1998, 15(8): 688-694
10. Plagemann A, Harder T, Kohlhoff R, Fahrenkrog S, Rodekamp E, Franke K, Dudenhausen J W. Impact of early neonatal breast-feeding on psychomotor and neuropsychological development in children of diabetic mothers [J]. Diabetes Care, 2005, 28(3): 573-578
11. McCance R A. Food growth and time [J]. Lancet, 1962, 2: 271-272
12. Hahn P. Effect of litter size on plasma cholesterol and insulin and some liver and adipose tissue enzymes in adult rodents[J]. J Nutr, 1984, 114(7): 1231-1234
13. Young J B. Effects of litter size on sympathetic activity in young adult rats[J]. Am J Physiol Regul Integr Comp Physiol, 2002, 282: R1113-R1121
14. Holmes J M, Duffner L A. The effect of litter size on normal retinal vascular development in the neonatal rat[J]. Curr Eye Res, 1995, 14(8): 737-740
15. Koldovsky O, Hahn P, Hromadova M, Krecek J, Macho L. Late effects of early nutritional manipulations[J]. Physiol Res, 1995,44(6):357-360
16. Langley S C, Browne R F, Jackson A A. Altered glucose tolerance in rats exposed to maternal low protein diets in utero[J]. Comp Biochem Physiol, 1994, 109(2): 223-229
17. Langley S C, Jackson A A. Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets[J]. Clinical Science, 1994, 86(2): 217-222
18. Langley-Evans S C. Critical difference between two low protein diet protocols in the programming of hypertension in the rat[J]. Int J Food Sci Nutr, 2000, 51(1): 11-17
19. Kwong W Y, Wild A E, Roberts P, Willis A C, Fleming T P. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension[J]. Development, 2000, 127(19): 4195-4202
20. Petrie L, Duthie S J, Rees W D, McConnell J M. Serum concentrations of homocysteine are elevated during early pregnancy in rodent models of fetal programming[J]. Br J Nutr, 2002, 88(5): 471-477
21. Kind K L, Clifton P M, Grant P A, Owens P C, Sohlstrom A, Roberts C T, Robinson J S, Owens J A. Effect of maternal feed restriction during pregnancy on glucose tolerance in the adult guinea pig[J]. Am J Physiol Regul Integr Comp Physiol, 2003, 284(1): R140-R152
22. Kind K L, Clifton P M, Katsman A I, Tsiounis M, Robinson J S, Owens J A. Restricted fetal growth and the response to dietary cholesterol in the guinea pig[J]. Am J Physiol, 1999, 277(6Pt2): R1675-R1682
23. Garofano A, Czernichow P, Breant B. In utero undernutrition impairs rat beta-cell development [J]. Diabetologia, 1997,40(10): 1231-1234
24. Molendi-Coste O, Grumolato L, Laborie C, Lesage J, Maubert E, Ghzili H, Vaudry H, Anouar Y, Breton C, Vieau D. Maternal perinatal undernutrition alters neuronal and neuroendocrine differentiation in the rat adrenal medulla at weaning[J]. Endocrinology, 2006, 147(6): 3050-3059
25. Lesage J, Dufourny L, Laborie C, Bernet F, Blondeau B, Avril I, Breant B, Dupouy J P. Perinatal malnutrition programs sympathoadrenal and hypothalamic-pituitary-adrenal axis responsiveness to restraint stress in adult male rats[J]. J Neuroendocrinol, 2002, 14(2): 135-143
26. Bieswal F, Ahn M T, Reusens B, Holvoet P, Raes M, Rees W D, Remacle C. The importance of catch-up growth after early malnutrition for the programming of obesity in male rat. Obesity (Silver Spring), 2006,14(8): 1330-1343
27. Vickers M H, Breier B H, Cutfield W S, Hofman P L, Gluckman P D. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition[J]. Am J Physiol Endocrinol Metab, 2000, 279(1): E83-E87
28. Mericq V. Low birth weight and endocrine dysfunction in postnatal life[J]. Pediatr Endocrinol Rev, 2006, 4(1): 3-14
29. Blondeau B, Avril I, Duchene B, Breant B. Endocrine pancreas development is altered in foetuses from rats previously showing intrauterine growth retardation in response to malnutrition[J]. Diabetologia, 2002,45(3): 394-401
30. Kanitz E, Tuchscherer M, Puppe B, Tuchscherer A, Stabenow B. Consequences of repeated early isolation in domestic piglets (Sus scrofa) on their behavioural, neuroendocrine, and immunological responses[J]. Brain Behav Immun, 2004, 18(1): 35-45
31. Canlon B, Li H, Olson L, Hultcrantz M, Borg E. Stage dependent development of intraocular cochlear grafts[J]. Hear Res, 1992, 64(1): 142-148
32. De Blasio M J, Gatford K L, McMillen I C, Robinson J S, Owens J A. Placental restriction of fetal growth increases insulin action, growth, and adiposity in the young lamb[J]. Endocrinology, 2007, 148(3): 1350-1358
33. Bakker J M, Schmidt E D, Kroes H, Kavelaars A, Heijnen C J, Tilders F J, van Rees E P. Effects of short-term dexamethasone treatment during pregnancy on the development of the immune system and the hypothalamo-pituitary adrenal axis in the rat[J]. J Neuroimmunol, 1995, 63(2): 183-191
34. Wu G, Bazer F W, Cudd T A, Meininger C J, Spencer T E. Maternal Nutrition and Fetal Developmen[J]. J Nutr, 2004, 134(9): 2169-2172
35. Petry C J, Ozanne S E, Hales C N. Programming of intermediary metabolism[J]. Mol Cell Endocrinol, 2001, 185(1-2): 81-91
36. Hales C N, Barker D J. Type 2 (non-insulin-dependant) diabetes mellitus: the thrifty phenotype hypothesis[J]. Diabetologia, 1992, 35(7): 595-601
37. Wells J C. The thrifty phenotype hypothesis: thrifty offspring or thrifty mother?[J]. Theor Biol, 2003, 221(1): 143-161
38. Oliver M H, Harding J E, Breier B H, Gluckman PD. Fetal insulin - like growth factor (IGF) - I and IGF - II are regulated differently by glucose and insulin in the sheep fetus [J]. Reprod Ferti Dev, 1996, 8(1): 167-172
39. Fowden A L, Hill D J. Intra-uterine programming of the endocrine pancreas. [J]Br Med Bull, 2001, 60: 123-142
40. Feil R. Environmental and nutritional effects on the epigenetic regulation of genes[J]. Mutat Res, 2006; 600(1-2): 46-57
41. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic[J]. Diabetes, 2005, 54(7): 1899-1906
42. Waterland R A, GarzaC. Potential mechanisms of metabolic imprinting that lead to chronic disease[J]. Am J Clin Nutr, 1999, 69(2): 179-197
43. Dolinoy D C, Weidman J R, Waterland R A, Jirtle RL. Maternal genistein alters coat color and protects A~(vy) mouse offspring from obesity by modifying the fetal epigenome[J]. Environ Health Perspect, 2006, 114(4): 567-572
1.Reusens B,Remacle C.Programming of the endocrine pancreas by the early nutritional environment[J].Int Biochem Cell B,2006,38(5-6):913-922
2.Byrne C D.Programming other hormones that affect insulin[J].Br Med Bull.,2001,60:153-171
3.Doherty A S,Temeles G L,Schultz R M.Temporal pattern of IGF-Ⅰ expression during mouse preimplantation embryogenesis[J].Mol Reprod Dev,1994,37(1):21-26
4.Harvey M,Kaye P L.Insulin increases the cell number of the immer cell mass and stimulates morphological development of mouse blastocysts in vitro[J].Develop,1990,110(3):963-967
5.Harvey M B,Kaye P L.Insulin stimulates protein synthesis in compacted mouse embryos[J].Endocrinology,1988,122(3):1182-1184
6.Tsai H D,Chang C C,Hsieh Y Y.Recombinant human leukemia inhibitory factor enhances the development of preimplantation mouse embryo in vitro[J].J Assist Reprod Genet,2000,17(6):352-355
7.Gardner H G,Kaye P L.Insulin increase cell numbers and morphological development in mouse pre-implantation embryos in vitro[J].Reprod Fertil Dev,1991,3(1):79-91
8.Kaye P L,Pemble L,Hobbs J G.Protein metabolism in preimplantation mouse embryos[J].Prog Clin Biol Res,1986,217B:103-106
9.Dunglison G F,Kaye P L.Insulin Regulates Protein Metabolism in Mouse Blastocysts[J].Mol Reprod Dev,1993,36(1):42-48
10.Draznin B,Solomons C C,Emler C A,Schalch D S,Sussman K E.Decreased insulin binding and degradation associated with depressed intracellular ATP content[J].Diabetes,1980,29(3):221-226
11.Draznin B.Molecular mechanisms of insulin resistance:serine phosphorylation of insulin receptor substrate-1 and increased expression of p85alpha:the two sides of a coin[J].Diabetes 2006,55(8):2392-7239
12.白照岱,刘凯,邴鲁军.胰岛素对小鼠早期胚胎体外发育的影响[J]生殖医学杂志,2004,13(5):286-290
13.Puscheck E E,Pergament E,Patel Y,Dreschler J,Rappolee D A.Insulin receptor substrate-1 is expressed at high levels in all cells of the peri-implantation mouse embryo[J].Mol Reprod Dev 1998,49(4):386-393
14.Bonner-Weir S.Perspective:postnatal pancreatic β cell growth endocrinology[J].Endocrinology,2000;141(6):1926-1929
15.Martin-Gronert M S,Ozanne S E.Programming of appetite and type 2 diabetes[J].Early Human Development, 2005, 81(12): 981-988
16. Pampfer S, de Hertogh R, Vanderheyden I, Michiels B, Vercheval M. Decreased inner cell mass proportion in blastocysts from diabetic rats[J]. Diabetes, 1990,39(4): 471-476
17. Beebe L F, Kaye P L. Maternal diabetes and retarded preimplantation development of mice[J]. Diabetes, 1991, 40(4): 457-461
18. Diamond M P, Moley K H, Pellicer A, Vaughn W K, DeCherney AH. Effects of streptozotocin- and alloxan-induced diabetes mellitus on mouse follicular and early embryo development[J]. J Reprod Fertil, 1989, 86(1): 1-10
19. De Hertogh R, Vanderheyden I, Pampfer S, Robin D, Dufrasne E, Delcourt J. Stimulatory and inhibitory effects of glucose and insulin on rat blastocyst development in vitro[J]. Diabetes, 1991, 40(5): 641-647
20. Mihalik J, Rehak P, Koppel J. The influence of insulin on the in vitro development of mouse and bovine embryos[J]. Physiol Res, 2000,49(3): 347-354
21. Plagemann A, Harder T, Franke K, Kohlhoff R. Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers[J]. Diabetes Care, 2002, 25(1): 16-22
22. Fernandez-Twinn D S, Ozanne S E, Ekizoglou S, Doherty C, James L, Gusterson B, Hales C N. The maternal endocrine environment in the low-protein model of intra-uterine growth restriction[J]. Br J Nutr, 2003, 90(4): 815-822
23. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
24. Verhaeghe J, Van Bree R, Van Herck, Laureys J, Bouillon R, Van Assche F A. C-peptide, insulin-like growth factors I and II, and insulin-like growth factor binding protein-I and II, and insulin-like growth factor binding protein-I in umbilical cord serum: Correlations with birth weight[J]. Am J Obstet Gynecol, 1993, 169(1): 89-97
25. Wiznitzer A, Reece E A, Homko C, Furman B, Mazor M, Levy J. Insulin-like growth factors, their binding proteins, and fetal macrosomia in offspring of nondiabetic pregnant women[J]. Am J Perinat, 1998, 15(1): 23-28.
26. Pedersen J. The Pregnant, Diabetic and Her Newborn.Problems and Management[M], 1997,Williams and Wilkins, Baltimore, MD, USA
27. Freinkel N. Banting Lecture 1980.Of pregnancy and progeny[J]. Diabetes, 1980,29(12):1023-1035
28. Van Assche F A, Holemans K, Aerts L. Fetal growth and consequences for later life[J]. J Perinat Med, 1998, 26(5): 337-346
29. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
30. Hamman R F. Genetic and environment determinants of non-insulin dependent diabetes mellitus[J]. Diabetes Metab Rev, 1992, 8(4):287-338
31. Martin A O, Simpson J L, Ober C, Freinkel N. Frequency of diabetes mellitus in mothers of probands with gestational diabetes, possible maternal influence on the predisposition to gestational diabetes[J]. Am J Obstet Gynecol. 1985, 151(4): 471-475
32. Dorner G, Steindel E, Thoelke H, Schliack V. Evidence for decreasing prevalence of diabetes mellitus in childhood apparently produced by prevention of hyperinsulinism in the foetus and newborn[J]. Exp Clin Endocr Diab, 1984, 84(2): 134-142
33. Dorner G, Plagemann A, Reinagel H. Familial diabetes aggregation in type 2 diabetics, gestational diabetes as apparent risk factor for increased diabetes susceptibility in the offspring[J]. Exp Clin Endocr Diab, 1987, 89(1): 84-90
34. Saini KS, Thompson C, Winterford C M, Walker N I, Cameron D P. Streptozotocin at low doses induces apoptosis and at high doses causes necrosis in a murine[J]. Biochem.Mol.Biol.Int, 1996, 39(6): 1229-1236
35. Ito M, Kondo Y, Nakatani A, Hayashi K, Naruse A. Characterization of low dose streptozotocin-induced progressive diabetes in mice[J]. Environ Toxicol Phar, 2001, 9(3): 173-184
36. Kervran A, Guillaume M, Jost A. The endocrine pancreas of the fetus from diabetic pregnant rat[J]. Diabetologia, 1978, 15(5): 387-393
37. Aerts L, Van Bree R, Feytons V, Rombauts W, Van Assche FA.Plasma amino acids in diabetic pregnant rats and in their fetal and adult offspring[J]. Biol Neonate, 1989, 56(1): 31-39
38. Gauguier D, Bihoreau M T, Picon L, Ktorza A. Insulin secretion in adult rats after intrauterine exposure to mild hyperglycemia during late gestation[J]. Diabetes, 1991,40 Suppl 2:109-114
39. Philipps A F, Rosenkrantz T S, Grunnet M L, Connolly M E, Porte P J, Raye J R. Effects of fetal insulin secretory deficiency on metabolism in fetal lamb[J]. Diabetes, 1986,35(9):964-72
40. Schroeder R E, Doria-medina C L, Das U G, Sivitz W I, Devaskar S U. Effect of maternal diabetes upon fetal rat myocardial and skeletal muscle glucose transporters[J]. Pediatr Res, 1997, 41(1):11-19
41. Canavan J P, Goldspink D F. Maternal diabetes in rats II. Effects on fetal growth and protein turnover[J]. Diabetes, 1988,37(12): 1671-1677
42. Holemans K, Aerts L, Van Assche F A. Evidence for an insulin resistance in the adult offspring of streptozotocin-diabetic pregnant rats[J]. Diabetologia, 1991, 34(2): 81-85
43. Holemans K, Aerts L, Van Assche F A. Absence of pregnancy-induced alterations in tissue insulin sensitivity in the offspring of diabetic rats[J]. J Endocrinol, 1991,131(3): 387-393.
44. Boujendar S, Reusens B, Merezak S, Ann M T, Arany E, Hill D, Remacle C. Taurine supplementation to a low protein diet during fetal and early postnatal life restores a normal proliferation and apoptosis of rat pancreatic islets[J]. Diabetologia, 2002, 45(6): 856-866
45. Petrik J, Reusens B, Arany E, Remacle C, Coelho C, Hoet J J, Hill D J. A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor II[J]. Endocrinology, 1999, 140(10): 4861-4873
46. Snoeck A, Remacle C, Reusens B, Hoet J J.Effect of low protein diet during pregnancy on the fetal rat endocrine pancreas[J]. Biol Neonate, 1990, 57(2): 107-118
47. Cherif H, Reusens B, Dahri S, Remacle C. A protein restricted diet during pregnancy alters in vitro insulin secretion from islets of fetal Wistar rats[J]. J Nutr, 2001, 131(5), 1551-1559
48. Blondeau B, Lesage J, Czernichow P, Dupouy J P, Breant B. Glucocorticoids impair fetal β cell development in rat[J].Am J Phys, 2001, 281(3), E592-E599
49. Garofano A, Czernichow P, Breant B. In utero undernutrition impairs rat β-cell development[J]. Diabetologia, 1997, 40(10), 1231-1234
50. Garofano A, Czernichow P, Breant B. Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat[J]. Diabetologia, 1998, 41(9): 1114-1120
1.Feil R.Environmental and nutritional effects on the epigenetic regulation of genes[J].Mutat Res,2006,600(1-2):46-57
2.Walter J,Paulsen M.Imprinting and disease[J].Semin Cell Dev Biol,2003,14(1):101-110
3.McGrath J,Solter D.Completion of mouse embryogenesis requires both the maternal and paternal genomes[J].Cell,1984,37(1):179-183
4.Surani M A H,Barton S C,Norris M L.Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis[J].Nature,1984,308(5959):548-550
5.李宏军,郭应禄,张志文.印迹基因及其对胚胎发育的调控[J].生物化学与生物物理进展,1999,26(1):19-22
6.Hajkova P,Erhardt S,Lane N,Haaf T,E1-Maarri O,Reik W,Walter J,Surani M A.Epigenetic reprogramming in mouse primordial germ cells[J].Mech Dev,2002,117(1-2):15-23
7.Barlow D P.Gametic imprinting in mammals[J].Science,1995,270(5242):1610-1613
8.Wrenzycki C,De Sousa P,Overstrom E W,Duby R T,Herrmann D,Watson A J,Niemann H,O'Callaghan D,Boland M P.Effects of superovulated heifer diet type and quantity on relative mRNA abundances and pyruvate metabolism in recovered embryos[J].J.Reprod.Fertil,2000,118(1):69-78
9.Thompson SL,Konfortova G,Gregory R I,Reik W,Dean W,Feil R.Environmental effects on genomic imprinting in mammals[J].Toxicol Lett,2001,120(1-3):143-150
10.Holm P,Walker S K,Seamark R F.Embryo viability,duration of gestation and birth weight in sheep after transfer of in vitro matured and in vitro fertilized zygotes cultured in vitro or in vivo[J].J Reprod Fertil,1996,107(2):175-181
11.Young L E,Sinclair K D,Wilmut I.Large offspring syndrome in cattle and sheep[J].Rev Reprod,1998,3(3):155-163.
12.Khosla S,Dean W,Brown D,Reik W,Feil R.Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes[J].Biol Reprod,2001,64(3):918-926
13.Sinclair K D,Young L E,Wilmut I,McEvoy T G In utero overgrowth in ruminants following embryo culture:Lessons from mice and a warning to men[J].Hum Reprod,2000,15,Supplement 5:68-86
14.李云龙,刘春巧主编著.动物发育生物学[M].山东科学技术出版,2003,549-561
15.Pteifer K,Tilghman S M.Allele-specific gene expression in mammals:the curious case of the imprinted RNAs[J].Genes Dev,1994,8(16):1867-1874
16.Bartolomei M S,Zemel S,Tilghman S M.Parental imprinting of the mouse H19 gene[J].Nature,1991,351(6322):153-155
17.DeChiara T M,Robertson E J,Efstratiadis A.Parental imprinting of the mouse insulin-like growth factor Ⅱ gene[J].Cell,1991,64(4):849-859
18.Villar A J,Eddy E M,Pedersen R A.Developmental regulation of genomic imprinting during gametogenesis[J],Dev Biol,1995,172(1):264-271
19.Weber M,Milligan L,Delalbre A,Antoine E,Brunel C,Cathala G,Forne T.Extensive tissue-specific variation of allelic methylation in the Igf2 gene during mouse fetal development:relation to expression and imprinting[J].Mech Develop,2001,101(1-2):133-141
20.Doherty A S,Mann M R,Tremblay K D,Bartolomei M S,Schultz R M.Differential Effects of Culture on Imprinted H19 Expression in the Preimplantation Mouse Embryo[J].Biol Reprod,2000,62(6),1526-1535
21.Maher E R,Reik W.Beckwith-Wiedemann syndrome:imprinting in clusters revisited[J].J Clin Invest,2000,105(3):247-252
22.Eggenschwiler J,Ludwig T,Fisher P,Leighton P A,Tilghman S M,Efstratiadis A.Mouse mutant embryos overexpressing IGF-Ⅱ exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes[J].Genes Dev,1997,11(23):3128-3142
23.Reik W,Bowden L,Constancia M,Dean W,Fell R,Forne T,Kelsey G,Maher E,Moore T,Sun F L,Walter J.Regulation of Igf2 imprinting in development and disease[J].Int J Dev Biol,1996,Suppl 1:53S-54S
24.Jirtle R L,Sander M,Barrett J C.Genomic imprinting and environmental disease susceptibility[J].Environ Health Perspect,2000,108(3):271-278
25.杨玉华,何小兵.印迹基因IGF2和H19的研究进展[J].国外医学分子生物学分册,2002,24(4):254-256
26.Kwong W Y,Miller D J,Ursell E,Wild A E,Wilkins A P,Osmond C,Anthony F W,Fleming T P.Imprinted gene expression in the rat embryo-fetal axis is altered in response to periconceptional maternal low protein diet[J].Reproduction,2006,132(2):265-277
27.Howell C Y,Bestor T H,Ding F,Latham K E,Mertineit C,Trasler J M,Chaillet J R.Genomic imprinting disrupted by a maternal effect mutation in the Dnmtl gene[J].Cell,2001,104(6):829-838
28.Li E,Beard C,Jaenisch R.Role for DNA methylation in genomic imprinting[J].Nature,1993,366(6453):362-365
1.Feil R.Environmental and nutritional effects on the epigenetic regulation of genes[J].Mutat Res 2006,600(1-2):46-57.
2.Razin A,Shemer R.DNA methylation in early development[J].Hum Mol Genet,1995,4 Spec No:1751-1755
3.John R M,Surani M A.Imprinted genes and regulation of gene expression by epigenetic inheritance[J].Curr Opin Cell Biol,1996,8(3):348-353
4.Dolinoy D C,Weidman J R.,Jirtle R L.Epigenetic gene regulation:Linking early developmental environment to adult disease[J].Reprod Toxicol,2007,23(3):297-307
5.Constancia M,Pickard B,Kelsey G,Reik W.Imprinting mechanisms[J].Genome Res,1998,8(9):881-900
6.Tilghman S M.The sins of the fathers and mothers:genomic imprinting in mammalian development [J].Cell,1999,96:185-193
7.Jaenisch R,Bird A.Epigenetic regulation of gene expression:how the genome integrates intrinsic and environmental signals[J].Nat Genet,2003,33 Suppl:245-254
8.Chaillet J R,Vogt T F,Beier D R,Leder P.Parental-specific methylation of an imprinted transgene is established during gametogenesis and progressively changes during embryogenesis[J].Cell,1991,6(1):77-83
9.Chaillet J R,Bader D S,Leder P.Regulation of genomic imprinting by gametic and embryonic processes[J].Genes Dev,1995,9(10):1177-1187
10.Hajkova P,Erhardt S,Lane N,Haaf T,EI-Maarri O,Reik W,Walter J,Surani MA.Epigenetic reprogramming in mouse primordial germ cells[J].Mech Dev,2002,117(1-2):15-23
11.Kay G F,Penny G D,Patel D,Ashworth A,Brockdorff N,Rastan S.Expression of Xist during Mouse Development Suggests a Role in the Initiation of X Chromosome Inactivation[J].Cell,1993,72(2):171-182
12.岳占碰,杨增明.哺乳动物基因印迹及其与胚胎发育的关系[J],动物学杂志,1999,34(4):56-59
13.Schoenherr C J,Levorse J M,Tilghman S M.CTCF maintains differential methylation at the Igf2/H19 locus[J].Nat Genet,2003,33(1):66-69
14.Fedoriw A M,Stein P,Svoboda P,Schultz RM,Bartolomei MS.Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting[J].Science,2004,303(5655):238-240
15.Bell A C,Felsenfeld G.Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene[J].Nature,2000,405(6785):482-485
16.Hark A T,Schoenherr C J,Katz D J,Ingrain RS,Levorse JM,Tilghman SM.CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus[J].Nature,2000,405(6785):486-489
17.程姗.印记控制区(ICR)的调控机制[J].生命的化学,2004,24(5):383-386
18.Walter J,Paulsen M.Imprinting and disease[J].Semin Cell Dev Biol,2003,14(1):101-110
19.尹斌,沈岩.DNA的甲基化修饰与DNA甲基转移酶[J].国外医学遗传学分册,2001,24(1):5-8
20.Hata K,Okano M,Lei H,Li E.Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice[J].Develop,2002,129(8):1983-1993
21.Yoder J A,Soman N S,Verdine G L,Bestor TH.DNA(cytosine-5)-methyltransferases in mouse cells and tissues.Studies with a mechanism-based probe[J].J Mol Biol,1997,270(3):385-395
22.Okano M,Bell D W,Haber D A,Li E.DNA methyltransferases Dnmt3a and Drtmt3b are essential for de novo methylation and mammalian development[J].Cell,1999(3),99:247-257
23.Bourc'his D,Xu GL,Lin CS,Bollman B,Bestor TH.Dnmt3L and the establishment of maternal genomic imprints[J].Science,2001,294(5551):2536-2539
24.Kaneda M,Okano M,Hata K,Sado T,Tsujimoto N,Li E,Sasaki H.Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting[J].Nature,2004,429(6994):900-903
25.Li E,Beard C,Jaenisch R.The Role of DNA Methylation in Genomic Imprinting[J].Nature,1993,366(6453):362-365
26.Leighton P A,Ingram R S,Eggenschwiler J,Efstratiadis A,Tilghman SM.Disruption of Imprinting Caused by Deletion of the H19 Gene Region in Mice[J].Nature,1995,375(6526):34-39
27.Barlow D P.Gametic Imprinting in Mammals[J].Science,1995,270(5242):1610-1613
28.Vassena R,Dee Schramm R,Latham K E.Species-dependent expression patterns of DNA methyltransferase genes in mammalian oocytes and preimplantation embryos[J].Mol Reprod Dev,2005,72(4):430-436
29.Chen T,Ueda Y,Dodge JE,Wang Z,Li E.Establishment and Maintenance ofGenomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b[J].Mol Cell Biol,2003,23(16):5594-5605
30.LeGouy E,Thompson E M,Muehardt C,Renard JP.Differential preimplantation regulation of two mouse homologues of the yeast SWI2 protein[J].Dev Dyn,1998,212(1):38-48
31.Voncken J W,Schweizer D,Aagaard L,Sattler L,Jantsch MF,van Lohuizen M. Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status[J].J Cell Sci,1999,112(Pt 24):4627-4639
32.Robertson G T,Reisenauer A,Wright R,Jensen RB,Jensen A,Shapiro L,Roop RM.The Brucella abortus CcrM DNA methyltransferase is essential for viability,and its overexpression attenuates intracellular replication in murine macrophages[J].J Bacteriol,2000,182(12):3482-3489
33.赵冬梅.DNA甲基转移酶与早期胚胎发育[J].浙江大学学报(医学版),2005,34(3):281-284
34.Dolinoy D C,Weidman J R,Jirtle R L.Epigenetic gene regulation:Linking early developmental environment to adult disease[J].Reprod Toxicol,2007,23(3):297-307.
35.Thompson S L,Konfortova G,Gregory R I,Reik W,Dean W,Feil R.Environmental effects on genomic imprinting in mammals[J].Toxicol Lett,2001,120(1-3):143-150
36.Khosla S,Dean W,Brown D,Reik W,Feil R.Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes[J].Biol Reprod,2001,64(3):918-926
37.Sasaki H,Ishihara K,Kato R.Mechanisms of Igf2/H19 imprinting:DNA methylation,chromatin and long-distance gene regulation[J].J.Biochem.(Tokyo),2005,127(5):711-715
38.Doherty AS,Mann MR,Tremblay KD,Bartolomei MS,Schultz RM.Differential Effects of Culture on Imprinted H19 Expression in the Preimplantation Mouse Embryo[J].Biol Reprod,2000,62(6):1526-1535
39.Ungaro P,Casola S,Vernucci M,Pedone PV,Bruni CB,Riccio A.Relaxation of insulin-like growth factor-2 imprinting in rat cultured cells[J].Mol Cell Endocrinol,1997,135(2):153-163
40.Waterland R A,Dolinoy D C,Lin J R,Smith CA,Shi X,Tahiliani KG.Maternal methyl supplements increase offspring DNA methylation at Axin Fused[J].Genesis,2006,44(9):401-406
41.Dolinoy D C,Weidman J R,Waterland R A,Jirtle RL.Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome[J].Environ Health Perspect,2006,114(4):567-572
42.Okoji R S,Yu R C,Maronpot R R,Froines JR.Sodium arsenite administration via drinking water increases genome-wide and Ha-ras DNA hypomethylation in methyl-deficient C57BL/6J mice[J].Carcinogenesis,2002,23(5):777-85
43.Wu Q,Ohsako S,Ishimura R,Suzuki JS,Tohyama C.Exposure of Mouse Preimplantation Embryos to 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) Alters the Methylation Status of Imprinted Genes H19 and Igf2[J].Biol Reprod,2004,70(6):1790-1797
44.Weaver I,Champagne F A,Brown S,Dymov S,Sharma S,Meaney MJ,Szyf M.Reversal of maternal programming of stress responses in adult offspring through methyl supplementation[J].J Neurosci,2005,25(47):11045-11054
45.Zhu B,Huang X,Chen J,Lu Y,Chen Y,Zhao J.Methylation changes of H19 gene in sperms of X-irradiated mouse and maintenance in offspring[J].Biochem and Biophy Res Commu,2006,340(1):83-89
46.Koturbash I,Baker M,Loree J,Kutanzi K,Hudson D,Pogribny I,Sedelnikova O,Bonner W,Kovalchuk O.Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo[J].Int J Radiat Oncol Biol Phys,2006,66(2):327-330
47.范保星.DNA甲基化检测方法[J].国外医学遗传学分册,2002,25(2):99-101
48.黄琼晓,金帆,黄荷凤.DNA甲基化的研究方法学[J].国外医学遗传学分册,2004,27(6):354-358
49.Wan Y,Wang Y,Luo J,Lu Z.Bisulfite modification of immobilized DNAs for methylation detection[J].Biosens Bioelectron,2007,22(11):2415-2421
50.Fraga MF,Esteller M.DNA methylation:a profile of methods and applications[J].Biotechniques,2002,33(3):632-649
1.Dufrane D,van Steenberghe M,Guiot Y,Goebbels RM,Saliez A,Gianello P.Streptozotocin-induced diabetes in large animals(pigs/primates):role of GLUT2 transporter and beta-cell plasticity 1998[J].Transplantation,2006,81(1):36-45
2.Gajdosik A,Gajdosikova A,Stefek M,Navarova.J,Hozova R.Streptozotocin-induced experimental diabetes in male Wistar rats[J].Gen Physiol Biophys,1999,18(Spec No):54-62
3.Harlan D M,Barnett M A,Abe R,Pechhold K,Patterson NB,Gray GS,June CH.Very-low-dose streptozotocin induces diabetes in insulin promoter-mB7-1 transgenic mice[J].Diabetes,1995,44(7):816-823
4.Richens E R,Behbehani K.The effect of adjuvants on immune function in the multi-low-dose streptozotocin model ofmurine diabetes[J].Int J Tissue React,1988,10(4):207-216
5.Noguchi S,Ohba Y,Oka T.Involvement of epidermal growth factor deficiency in pathogenesis of oligozoospermia in streptozotocin-induced diabetic mice[J].Endocrinology,1990,127(5):2136-2140
6.Diamond M P,Moley K H,Pellicer A,Vaughn WK,DeCherney AH.Effects of streptozotocin- and alloxan-induced diabetes mellitus on mouse follicular and early embryo development[J],J Reprod Fertil,1989,86(1):1-10
7.耿娅,纪丽曼,周兴军,等.链脲佐菌素致迟发型大鼠1型糖尿病模型的研究[J].河北医药,2006,28(10):906-907
8.宋立江,蒋东升,郭金铭,等.小鼠腹腔注射链脲佐菌素高血糖模型实验观察[J].中国卫生检验杂志,2006,16(10):1257-1258
9.杨巍,罗春元,于春雷,等.不同剂量STZ诱导小鼠糖尿病模型的发病机制[J].吉林大学学报(医学版),2006,32(3):432-435
10.梁海荣,唐焕文,罗皓,等.链脲佐菌素诱导糖尿病大鼠肾病模型的建立应用[J].预防医学,2006,12(3):133-135
11.Ito M,Kondo Y,Nakatani A,Hayashi K,Naruse A..Characterization of low dose streptozotocin-induced progressive diabetes in mice[J].Environ Toxicol Phar,2001,9(3):173-184
12.Aerts L,Holemans K,Van Assche F A.Maternal diabetes during pregnancy:consequences for the offspring[J].Diabetes Metab Rev,1990,6(3):147-167
13.Reusens-Billen B,Remacle C,Daniline J,Hoet JJ.Cell proliferation in pancreatic islets of rat fetuses and neonates from normal and diabetic mothers.An in vitro and in vivo study[J].Horm Metab Res,1984,16(11):565-571
14. Aerts L, Vercruysse L, Van Assche F A. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats[J]. Diabetes Res Clin Pract, 1997,38(1): 9-19
15. Scarano W R, Messias A G, Oliva S U, Klinefelter GR, Kempinas WG. Sexual behaviour, sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats[J]. Int J Androl, 2006, 29(4): 482-488
16. Soudamani S, Malini T, Balasubramanian K. Effects of streptozotocin-diabetes and insulin replacement on the epididymis of prepubertal rats: histological and histomorphometric studies[J]. Endocr Res, 2005, 31(2): 81-98
17. Soudamani S, Yuvaraj S, Malini T, Balasubramanian K. Experimental diabetes has adverse effects on the differentiation of ventral prostate during sexual maturation of rats[J]. Anat Rec A Discov Mol Cell Evol Biol, 2005, 287(2): 1281-1289
18. Hassan A A, Hassouna M M, Taketo T, Gagnon C, Elhilali MM. The effect of diabetes on sexual behavior and reproductive tract function in male rats[J]. J Urol, 1993, 149(1): 148-154
19. Balasubramanian K, Sivashanmugam P, Thameemdheen S, Govindarajulu P. Effect of diabetes mellitus on epididymal enzymes of adult rats[J]. Indian J Exp Biol, 1991,29(10):907-909
20. Cameron D F, Rountree J, Schultz R E, Repetta D, Murray FT. Sustained hyperglycemia results in testicular dysfunction and reduced fertility potential in BBWOR diabetic rats[J]. Am J Physiol, 1990, 259 (6 Pt 1): E881-E889
21. Seethalakshmi L, Menon M, Diamond D. The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat[J]. J Urol, 1987, 138(1): 190-194
22. Chang A S, Dale A N, Moley K H. Maternal diabetes adversely affects preovulatory oocyte maturation, development, and granulosa cell apoptosis[J]. Endocrinology, 2005,146(5): 2445-2453
23. Colton S A, Humpherson P G, Leese H J, Downs SM. Physiological changes in oocyte-cumulus cell complexes from diabetic mice that potentially influence meiotic regulation[J]. Biol Reprod, 2003, 69(3): 761-770
24. Colton S A, Pieper G M, Downs S M. Altered meiotic regulation in oocytes from diabetic mice[J]. Biol Reprod, 2002, 67(1): 220-231
25. Vesela J, Cikos S, Hlinka D, Rehak P, Baran V, Koppel J. Effects of impaired insulin secretion on the fertilization of mouse oocytes[J]. Hum Reprod, 1995,10(12): 3233-3236
26. Wi J K, Kim J K, Youn J H. Reduced glucose clearance as the major determinant of postabsorptive hyperglycemia in diabetic rats[J]. Am J Physiol, 1998,274 (2 Pt 1): E257-E264
27. Tay Y C, Wang Y, Kairaitis L, Rangan GK, Zhang C, Harris DC. Can murine diabetic nephropathy be separated from superimposed acute renal failure?[J]. Kidney Int, 2005, 68(1): 391-398
28. Van Dam P S, Van Asbeck B S, Bravenboer B, Van Oirschot JF, Marx JJ, Gispen WH. Nerve conduction and antioxidant levels in experimentally diabetic rats: effects of streptozotocin dose and diabetes duration[J]. Metabolism, 1999, 48(4): 442-447
29. Jian K, Fok E, Cam M C, Sambandam N, Yao J, Rodrigues B. Susceptibility of spontaneously hypertensive rats to the diabetogenic effects of streptozotocin[J]. J Physiol Pharmacol, 1996, 74(11): 1215-1221
30. Jin T, Nordberg G, Sehlin J, Vesterberg O. Protection against cadmium-metallothionein nephrotoxicity in streptozotocin-induced diabetic rats: role of increased metallothionein synthesis induced by streptozotocin[J]. Toxicology, 1996, 106(1-3): 55-63
31. Kaufman C R, Catanese V M. Pre- and post-translational regulation of renal insulin-like growth factor binding protein-1 in insulin-deficient diabetes[J]. J Investig Med, 1995,43(2): 178-186
32. Miura H, Iguchi A, Uemura K, Yatomi A, Tamagawa T, Sakamoto N. CNS stimulation does not affect hepatic venous glucose concentration in severely diabetic rats[J]. Am J Physiol, 1991, 260(3 Pt 1): E440-E446
33. Tremblay R R, Trottier L, Abele V, Nadeau A, Gagnon P. Effect of streptozotocin-induced diabetes on insulin binding parameters in adult rat testis[J]. Andrologia, 1985, 17(6): 587-591
34. Rehak P, Mihalik J, Vesela J, Cikos S, Baran V, Koppel J. Effects of impaired maternal insulin secretion on preimplantation embryo development in ICR mice[J]. Physiol Res, 1996, 45(6): 453-458
35. Beebe L F, Kaye P L. Maternal diabetes and retarded preimplantation development of mice[J]. Diabetes, 1991, 40(4): 457-461
1. Ravelli A C, van der Meulen J H, Michels R P, Osmond C, Barker DJ, Hales CN, Bleker OP. Glucose tolerance in adults after prenatal exposure to famine[J]. Lancet, 1998, 351(9097): 173-177
2. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
3. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J]. Diabet Med, 1998, 15(8): 688-694
4. Ito M, Kondo Y, Nakatani A, Hayashi K, Naruse A. Characterization of low dose streptozotocin-induced progressive diabetes in mice[J]. Environ Toxicol Phar, 2001, 9(3): 173-184
5. Pinter E, Reece E A, Leranth C Z, Sanyal M K, Hobbins J C, Mahoney MJ , Naftolin F. Yolk sac failure in embryopathy due to hyperglycemia: ultrastructural analysis of yolk sac differentiation associated with embryopathy in rat conceptuses under hyperglycemic conditions[J]. Teratology, 1986, 33(1): 73-84
6. Hamman R F. Genetic and environment determinants of non-insulin dependent diabetes mellitus[J]. Diabetes Metab Rev, 1992, 8(4):287-338
7. Martin A O, Simpson J L, Ober C, Freinkel N. Frequency of diabetes mellitus in mothers of probands with gestational diabetes, possible maternal influence on the predisposition to gestational diabetes[J]. Am J Obstet Gynecol, 1985, 151(4): 471-475
8. Femandez-Twinn D S, Ozanne S E, Ekizoglou S, Doherty C, James L, Gusterson B, Hales C N. The maternal endocrine environment in the low-protein model of intra-uterine growth restriction [J]. Br J Nutr, 2003, 90(4): 815-822
9. Barker D J, Hales C N, Fall C H, Osmond C, Phipps K, Clark P M. Type 2 (non-insulin-dependent)diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth[J]. Diabetologia, 1993, 36(1): 62-67
10. Femandez-Twinn D S, Wayman A, Ekizoglou S, Martin M S, Hales C N, Ozanne S E. Maternal protein restriction leads to hyperinsulinemia and reduced insulin-signaling protein expression in 2i-mo-old female rat offspring[J]. Am J Physiol Regul Integr Comp Physiol, 2005, 288(2): R368-R373
11. Hales C N, Barker D J. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis[J]. Diabetologia, 1992, 35(7): 595-601
12. Plagemann A, Harder T, Lindner R, Melchior K, Rake A, Rittel F, Rohde W, Dorner G. Alterations of hypothalamic catecholamines in the newborn offspring of gestational diabetic mother rats[J]. Brain Res Dev Brain Res,1998, 109(2): 201-209
13. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J]. Diabet Med, 1998, 15(8): 688-694
14. Ozanne S E, Fernandez-Twinn D, Hales C N. Fetal growth and adult diseases[J]. Semin Perinatol, 2004, 28(1): 81-87
15. Hales C N, Barker D J. The thrifty phenotype hypothesis[J]. Br Med Bull, 2001, 60: 5-20
16. Plagemann A, Harder T, Franke K, et al. Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers[J]. Diabetes Care, 2002,25: 16-22
17. Reusens B, Remacle C. Programming of the endocrine pancreas by the early nutritional environment[J]. Int J Biochem Cell B, 2006, 38(5-6): 913-922
18. Aerts L, Van Assche F A. Intra-uterine transmission of disease[J]. Placenta, 2003, 24(10): 905-911
19 Aerts L, Van Assche F A. Animal evidence for the transgenerational development of diabetes meilitus[J]. Int J Biochem Cell B, 2006, 38(5-6): 894-903
20. Fernandez-Twinn D S, Ozanne S E. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome[J]. Physiol Behav, 2006, 88(3): 234-43
21. Aerts L, Vercruysse L, Van Assche F A. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats[J]. Diabetes Res Clin Pract, 1997, 38(1): 9-19
22. Reusens-Billen B, Remacle C, Daniline J, Hoet J J. Cell proliferation in pancreatic islets of rat fetuses and neonates from normal and diabetic mothers. An in vitro and in vivo study[J]. Horm Metab Res, 1984, 16(11): 565-71
23. Nold J L, Georgieff M K. Infants of diabetic mothers[J]. Pediatr Clin North Am, 2004, 51(3): 619-637
24. Nelson C A, Wewerka S, Thomas K M, Tribby-Walbridge S, deRegnier R, Georgieff M. Neurocognitive sequelae of infants of diabetic mothers[J]. Behav Neurosci, 2000, 114(5): 950-956
25. Lea R G, Andrade L P, Rae M T, Hannah L T, Kyle C E, Murray J F, Rhind S M, Miller D W. Effects of maternal undemutrition during early pregnancy on apoptosis regulators in the ovine fetal ovary[J]. Reproduction, 2006, 131(1): 113-124
26. Sun F, Kawasaki E, Akazawa S, Hishikawa Y, Sugahara K, Kamihira S, Koji T, Eguchi K. Apoptosis and its pathway in early post-implantation embryos of diabetic rats[J]. Diabetes Res Clin Pr, 2005, 67(2): 110-118
27. Phelan S A, Ito M, Loeken M R. Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis[J]. Diabetes, 1997, 46(7): 1189-1197
1. Lucas A. Programming by early nutrition: an experimental approach[J]. J Nutr, 1998, 128 (2 Suppl):401S-406S
2. Kwong W Y, Arthur E, Roberts P, Willis A C, Fleming T P. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension[J]. Development, 2000, 127(19): 4195-4202
3. Booth P J, Holm P, Callesen H. The effect of oxygen tension on porcine embryonic development is dependent on embryo type[J]. Theriogenology, 2005, 63(7):2040-2052
4. Tsai H D, Chang C C, Hsieh Y Y. Recombinant human leukemia inhibitory factor enhances the development of preimplantation mouse embryo in vitro[J]. J Assist Reprod Genet,2000,17(6):352-355
5. Gardner H G, Kaye P L. Insulin increase cell numbers and morphological development in mouse pre-implantation embryos in vitro[J]. Reprod Fertil Dev, 1991, 3(1): 79-91
6. Harvey, M B, Kaye, P L. Insulin stimulates protein synthesis in compacted mouse embryos[J].Endocrinology, 1988,122(3): 1182-1184
7. Harvey M, Kaye P L. Insulin increases the cell number of the immer cell mass and stimulates morphological development of mouse blastocysts in vitro[J]. Develop, 1990,110(3): 963-967
8. Kaye P L, Pemble L, Hobbs J G. Protein metabolism in preimplantation mouse embryos[J]. Prog Clin Biol Res, 1986,217B: 103-106
9. Dunglison G F, Kaye P L. Insulin Regulates Protein Metabolism in Mouse Blastocysts[J]. Mol Reprod Dev, 1993, 36(1): 42-48
10. Martin-Gronert M S, Ozanne S E. Programming of appetite and type 2 diabetes[J]. Early Hum Dev, 2005, 81(12): 981-988
11. Nagy A,Gertsenstein M,Vintersten K, Behringer R 2002. Manipulating the Mouse Embryo:A Laboratory Manual(Third edition ).Cold Spring Harbor Laboratory Press.
12. Bonner-Weir S. Perspective: postnatal pancreatic β cell growth endocrinology [J]. Endocrinology, 2000, 141(6): 1926-1929
13. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
14. Feil R. Environmental and nutritional effects on the epigenetic regulation of genes[J]. Mutat Res, 2006,600(5-6): 46-57
15.Barker D J,Hales C N,Fall C H,Osmond C,Phipps K,Clark P M.Type 2(non-insulin-dependent)diabetes mellitus,hypertension and hyperlipidaemia(syndrome X):relation to reduced fetal growth[J].Diabetologia,1993,36(1):62-67
16.Fernandez-Twinn D S,Wayman A,Ekizoglou S,Martin M S,Hales C N,Ozanne S E.Maternal protein restriction leads to hyperinsulinemia and reduced insulin-signaling protein expression in 21-mo-old female rat offspring[J].Am J Physiol Regul Integr Comp Physiol,2005,288(2):R368-R373
17.Hales C N,Barker D J.Type 2(non-insulin-dependent) diabetes mellitus:the thrifty phenotype hypothesis[J].Diabetologia,1992,35(7):595-601
18.Plagemann A,Harder T,Lindner R,Melchior K,Rake A,Rittel F,Rohde W,Dorner.Alterations of hypothalamic catecholamines in the newborn offspring of gestational diabetic mother rats[J].Brain Res Dev Brain Res,1998,109(2):201-209
19.Martyn C N,Hales C N,Barker D J,Jespersen S.Fetal growth and hyperinsulinaemia in adult life[J].Diabet Med,1998,15(8):688-694
20.Ozanne S E,Fernandez-Twinn D,Hales C N.Fetal growth and adult diseases[J].Semin Perinatol,2004,28(1):81-87
21.Hales C N,Barker D J.The thrifty phenotype hypothesis[J].Br Med Bull,2001,60:5-20
22.Plagemann A,Harder T,Franke K,Kohlhoff R.Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers[J].Diabetes Care,2002,25(1):16-22
23.Reusens B,Remacle C.Programming of the endocrine pancreas by the early nutritional environment[J].Int J Biochem Cell B,2006,38(5-6):913-922
24.Fernandez-Twinn D S,Ozarme S E,Ekizoglou S,Doherty C,James L,Gusterson B,Hales C N.The maternal endocrine environment in the low-protein model of intra-uterine growth restriction[J].Br J Nutr,2003,90(4):815-822
25.白照岱,刘凯,邴鲁军.胰岛素对小鼠早期胚胎体外发育的影响[J].生殖医学杂志,2004,13(5):286-290
26.Aerts L,Van Assche F A.Intra-uterine transmission of disease[J].Placenta,2003,24(10):905-911
27.Martin-Gronert M S,Ozanne S E.Maternal nutrition during pregnancy and health of the offspring[J].Biocheml Soc T,2006,34(5):779-782
28.Taylor P D,Khan I Y,Lakasing L,Dekou V,O'Brien-Coker I,Mallet A I,Hanson M A,Poston L.Uterine artery function in pregnant rats fed a diet supplemented with animal lard[J].Exp Physiol,2003,88(3):389-398
29.Aerts L,Van Assche F A.Animal evidence for the transgenerational development of diabetes mellitus[J]. Int J Biochem Cell B, 2006, 38(5-6): 894-903
30. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic[J]. Diabetes, 2005, 54(7): 1899-1906
1. Reusens-Billen B, Remacle C, Daniline J, Hoet J J. Cell proliferation in pancreatic islets of rat fetuses and neonates from normal and diabetic mothers. An in vitro and in vivo study [J]. Horm Metab Res, 1984, 16(11): 565-571
2. Kervran A, Guillaume M, Jost A. The endocrine pancreas of the fetus from diabetic pregnant rat[J]. Diabetologia, 1978, 15(5): 387-393
3. Aerts L, Vercruysse L, Van Assche F A. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats[J]. Diabetes Res Clin Pract, 1997, 38(1): 9-19
4. Tay Y C, Wang Y, Kairaitis L, Rangan G K, Zhang C, Harris D C. Can murine diabetic nephropathy be separated from superimposed acute renal failure?[J] Kidney Int, 2005, 68(1): 391-398
5. Wi J K, Kim J K, Youn J H. Reduced glucose clearance as the major determinant of postabsorptive hyperglycemia in diabetic rats[J]. Am J Physiol, 1998, 274(2 Pt 1): E257-E264
6. Jian K, Fok E, Cam M C, Yao J, Rodrigues B. Susceptibility of spontaneously hypertensive rats to the diabetogenic effects of streptozotocin[J]. Can J Physiol Pharmacol, 1996,74(11):1215-1221
7. Soudamani S, Yuvaraj S, Malini T, Balasubramanian K. Experimental diabetes has adverse effects onthe differentiation of ventral prostate during sexual maturation of rats[J]. Anat Rec A Discov Mol Cell Evol Biol, 2005, 287(2): 1281-1289
8. Cameron D F, Rountree J, Schultz R E, Repetta D, Murray F T. Sustained hyperglycemia results in testicular dysfunction and reduced fertility potential in BBWOR diabetic rats[J]. Am J Physiol, 1990, 259(6 Pt 1):E881-E889
9. Beebe L F, Kaye P L. Maternal diabetes and retarded preimplantation development of mice[J]. Diabetes, 2001, 40(4): 457-461
10. Diamond M P, Moley K H, Pellicer A, Vaughn W K, DeCherney A H. Effects of streptozotocin and alloxan-induced diabetes mellitus on mouse follicular and early embryo development[J]. J Reprod Fertil, 1989, 86(1):1-10.
11. De Hertogh R, Vanderheyden I, Pampfer S, Robin D, Dufrasne E, Delcourt J. Stimulatory and inhibitory effects of glucose and insulin on rat blastocyst development in vitro[J]. Diabetes, 1991, 40(5): 641-647
12. Mihalik J, Rehak P, Koppel J. The influence of insulin on the in vitro development of mouse and bovine embryos[J]. Physiol Res, 2000, 49(3): 347-354
13. Lea R G, Andrade L P, Rae M T, Hannah L T, Kyle C E, Murray J F, Rhind S M, Miller D W. Effects of maternal undemutrition during early pregnancy on apoptosis regulators in the ovine fetal ovary[J]. Reproduction, 2006, 131(11): 113-124
14. Rehak P, Mihalik J, Vesela J, Cikos S, Baran V, Koppel J. Effects of impaired maternal insulin secretion on preimplantation embryo development in ICR mice[J]. Physiol Res, 1996, 45(6): 453-458
15. Sadler T W. Effects of maternal diabetes on early embryogenesis: I. The teratogenic potential of diabetic serum[J]. Teratology, 1980, 21(3): 339-347
16. Sadler T W. Effects of maternal diabetes on early embryogenesis: II. Hyperglycemia-induced exencephaly[J]. Teratology, 1980, 21(3): 349-356
17．李云龙,刘春巧．动物发育生物学[M]．山东,2003：549-561
18. Bartolomei M S, Zemel S, Tilghman S M. Parental imprinting of the mouse H19 gene[J]. Nature, 1991,351(6322): 153-155
19. DeChiara T M, Robertson E J, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene[J]. Cell, 1991,64(4):849-859
20. Dunglison G F, Kaye P L. Insulin Regulates Protein Metabolism in Mouse Blastocysts[J]. Mol ReprodDev, 1993, 36(1): 42-48
21. Khosla S, Dean W, Brown D, Reik W, Feil R. Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes[J]. Biol Reprod, 2001,64(3): 918-926
22.Thorvaldsen J L, Duran K, Bartolomei M S. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2[J]. Genes Dev, 1998,12(23): 3693-3702
23. Hsieh C L. Dynamics of DNA methylation pattern[J]. Curr Opin Genet Dev, 2000,10(2): 224-228
24. Feil R, Walter J, Allen N D, Reik W. Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes[J]. Develop, 1994,120(10): 2933-2943
25. Ungaro P, Casola S, Vernucci M, Pedone P V, Bruni C B, Riccio A. Relaxation of insulin-like growth factor-2 imprinting in rat cultured cells[J].Mol Cell Endocrinol, 1997,135(2):153-63
26.Thorvaldsen J L, Duran K L, Bartolomei M S. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2[J]. Genes Dev, 1998, 12(23):3693-3702
27. Wu Q, Ohsako S, Ishimura R, Suzuki J S, Tohyama C. Exposure of Mouse Preimplantation Embryos to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Methylation Status of Imprinted Genes H19 and Igf2[J]. Biol Reprod, 2004, 70(6): 1790-1797
28. Livak K J, Schmittgen T D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T) )method[J]. Methods, 2001, 25 (4): 402-408
29. Vambergue A, Fajardy I, Dufour P, Valat A S, Vandersippe M, Fontaine P, Danze P M, Rousseaux J. No loss of genomic imprinting of IGF-II and H19 in placentas of diabetic pregnancies with fetal macrosomia[J]. Growth Horm IGF Res, 2007, 17(2): 130-136
30. Zhu B, Huang X, Chen J, Lu Y, Chen Y, Zhao J. Methylation changes of H19 gene in sperms of X-irradiated mouse and maintenance in offspring[J]. Biochem and Biophy Res Commu, 2006, 340(1): 83-89
31. Junien C, Gallou-Kabani C, Vige A, Gross M S. Nutritional epigenomics of metabolic syndrome[J]. Med Sci (Paris), 2005, 21(4): 44-52
32. Junien C, Gallou-Kabani C, Vige A, Gross M S. Nutritionnal epigenomics: consequences of unbalanced diets on epigenetics processes of programming during lifespan and between generations[J]. Ann Endocrinol (Paris), 2005, 66(2 Pt 3): 2S19-28
33. Waterland R A, Dolinoy D C, Lin J R, Smith C A, Shi X, Tahiliani K G. Maternal methyl supplements increase offspring DNA methylation at Axin Fused[J]. Genesis, 2006, 44(9): 401-406
34. Doherty A S, Mann M R, Tremblay K D, Bartolomei M S, Schultz R M. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo[J]. Biol Reprod, 2000, 62(6): 1526-1535
1. Harvey M B, Kaye P L. Insulin stimulates protein synthesis in compacted mouse embryos[J]. Endocrinology, 1988,122(3): 1182-1184
2. Harvey M B, Kaye P L. Insulin increases the cell number of the immer cell mass and stimulates morphological development of mouse blastocysts in vitro[J]. Develop, 1990, 110(3): 963-967
3. Kaye P L, Pemble L B, Hobbs J G. Protein metabolism in preimplantation mouse embryos[J]. Prog Clin Biol Res, 1986, 217B: 103-106
4. Gardner H G, Kaye P L. Insulin increase cell numbers and morphological development in mouse pre-implantation embryos in vitro[J]. Reprod Fertil Dev, 1991, 3(1): 79-91
5. Dunglison G F, Jane S D, McCaul T F, Chad J E, Fleming T P, Kaye P L. Stimulation of endocytosis in mouse blastocysts by insulin: a quantitative morphological analysis[J]. J Reprod Fertil, 1995, 105(1): 115-123
6. Rosenblum I Y, Mattson B A, Heyner S. Stage-specific insulin binding in mouse preimplantation embryos[J]. Dev Biol, 1986,116(1): 261-263
7. Kaye P L, Bell K L, Beebe L F, Dunglison G F, Gardner H G, Harvey M B. Insulin and the insulin-like growth factors (IGFs) in preimplantation development[J]. Reprod Fertil Dev, 1992, 4(4): 373-386
8. Mattson B A, Rosenblum I Y, Smith R M, Heyner S. Autoradiographic evidence for insulin and insulin-like growth factor binding to early mouse embryo[J]. Diabetes, 1988,37(5):585-589
9. Dunglison G F, Kaye P L. Insulin Regulates Protein Metabolism in Mouse Blastocysts[J]. Mol Reprod Dev, 1993, 36(1): 42-48
10. Bartolomei M S, Zemel S, Tilghman S M. Parental imprinting of the mouse H19 gene[J]. Nature, 1991,351(6322):153-155
11. DeChiara T M, Robertson E J, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene[J]. Cell, 1991,64(4):849-859
12. Khosla S, Dean W, Brown D, Reik W, Feil R. Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes[J]. Biol Reprod, 2001, 64(3): 918-926
13. Hsieh C L. Dynamics of DNA methylation pattem[J]. Curr Opin Genet Dev, 2000, 10(2): 224-228
14. Thorvaldsen J, Duran K L, Bartolomei M S. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2[J]. Genes Dev, 1998,12(23): 3693-3702
15. Feil R, Walter J, Allen N D. Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes[J]. Develop, 1994, 120(10): 2933-2943
16. Wu Q, Ohsako S, Ishimura R, Suzuki J S, Tohyama C. Exposure of Mouse Preimplantation Embryos to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Methylation Status of Imprinted Genes H19 and Igf2[J]. Biol Reprod, 2004, 70(6): 1790-1797
17. Zhu B, Huang X H, Chen J D, Lu Y C, Chen Y, Zhao J Y. Methylation changes of H19 gene in sperms of X-irradiated mouse and maintenance in offspring[J]. Biochem and Biophy Res Commu, 2006, 340(1): 83-89
18. Nagy A, Gertsenstein M, Vintersten K, Behringer R. Manipulating the Mouse Embryo:a laboratory manual 3rd ed .Cold Spring Harbor(NY):Cold Spring Harbor Laboratory Press. 2002.
19. Herrler A, Krusche C A, Beier H M. Insulin and insulin-like growth factor-I promote rabbit blastocyst development and prevent apoptosis[J]. Biol Reprod, 1998, 59(6): 1302-1310
20. Heyner S. Growth factors in preimplantation development: role of insulin and insulin-like growth factors[J]. Early Pregnancy. 1997, 3(3):153-163
21. Hiden U, Maier A, Bilban M, Ghaffari-Tabrizi N, Wadsack C, Lang I, Dohr G. Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy [J]. Diabetologia, 2006,49(1): 123-131
22. Kobayashi H, Suda C, Abe T, Kohara Y, Ikemura T, Sasaki H. Bisulfite sequencing and dinucleotide content analysis of 15 imprinted mouse differentially methylated regions (DMRs): paternally methylated DMRs contain less CpGs than maternally methylated DMRs[J]. Cytogenet Genome Res, 2006,113(1-4): 130-137
23. Serman A, Vlahovic M, Serman L, Bulic-Jakus F. DNA Methylation as a regulatory mechanism for gene expression in mammals[J]. Coll Antropol, 2006, 30(3): 665-671
24. Gebert C, Wrenzycki C, Herrmann D, Groger D, Reinhardt R, Hajkova P, Lucas-Hahn A, Carnwath J, Lehrach H, Niemann H. The bovine IGF2 gene is differentially methylated in oocyte and sperm DNA[J]. Genomics, 2006, 88(2): 222-229
25. Dean W, Bowden L, Aitchison A, Klose J, Moore T, Meneses J J, Reik W, Feil R. Altered imprinted gene methylation and expression in completely ES cell derived mouse fetuses: association with aberrant phenotypes[J]. Develop, 1998, 125(12): 2273-2282
26. Ungaro P, Casola S, Vernucci M, Pedone P V, Bruni C B, Riccio A. Relaxation of insulin-like growth factor-2 imprinting in rat cultured cells[J]. Mol Cell Endocrinol, 1997, 135(2): 153-163
27. Sasaki H, Ferguson-Smith A C, Shum A S, Barton S C, Surani M A. Temporal and spatial regulation of H19 imprinting in normal and uniparental mouse embryos[J]. Develop, 1995, 121(12): 4195-4202
28. Sinclair K D, Young L E, Wilmut I, McEvoy T G. In utero overgrowth in ruminants following embryo culture:Lessons from mice and a warning to men[J]. Hum Reprod, 2000, Supplement: 68-86
29. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic[J]. Diabetes, 2005, 54(7): 1899-1906
30. Waterland R A, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease[J]. Am J Clin Nutr, 1999, 69(2): 179-197
31. Cherif H, Reusens B, Dahri S Remacle C, Hoet J J. Stimulatory effects of taurine on insulin secretion by fetal rat islets cultured in vitro[J]. J Endocrinol, 1996,151(3): 501-506
32. Warnecke P M, Mann J R, Frommer M, Clark S J. Bisulfite Sequencing in Preimplantation Embryos: DNA Methylation Profile of the Upstream Region of the Mouse Imprinted H19 Gene[J]. Genomics, 1998,51(2): 182-190
33. Liu J, Nealon J G, Weinstein L S. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB [J]. Hum Mol Genet, 2005, 14(1): 95-102
34. Chen T, Ueda Y, Dodge J E, Wang Z, Li E. Establishment and Maintenance of Genomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b[J]. Mol Cell Biol, 2003, 23(16): 5594-5605
35. Okano M, Bell D W, Haber D A, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development[J]. Cell, 1999, 99(3): 247-257
36. Hata K, Okano M, Lei H, Li E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice[J]. Develop, 2002, 129(8): 1983-1993
1. Ravelli A C, van der Meulen J H, Michels R P, Osmond C, Barker D J, Hales C N, Bleker O P. Glucose tolerance in adults after prenatal exposure to famine[J]. Lancet, 1998(9097), 351: 173-177
2. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev. 1990, 6(3): 147-167
3. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J]. Diabet Med, 1998, 15(8): 688-694
4. Ito M, Kondo Y, Nakatani A, Hayashi K, Naruse A. Characterization of low dose streptozotocin-induced progressive diabetes in mice[J]. Environ Toxicol and Phar, 2001, 9(3): 173-184
5. Pinter E, Reece E A, Leranth C Z, Sanyal M K, Hobbins J C, Mahoney M J, Naftolin F. Yolk sac failure in embryopathy due to hyperglycemia: ultrastructural analysis of yolk sac differentiation associated with embryopathy in rat conceptuses under hyperglycemic conditions[J]. Teratology, 1986, 33(1): 73-84
6. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J].Diabet Med, 1998, 15(8): 688-694
7. Ozanne S E, Fernandez-Twinn D, Hales C N. Fetal growth and adult diseases[J]. Semin Perinatol, 2004, 8(1): 81-87
8. Phelan S A., Ito M., Loeken M R. Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis[J]. Diabetes, 1997, 46(7): 1189-1197
9. Sun F, Kawasakia E, Akazawac S, Hishikawa Y, Sugahara K, Kamihira S, Koji T, Eguchi K. Apoptosis and its pathway in early post-implantation embryos of diabetic rats Diabetes[J]. Res and Clin Pr, 2005, 67(2): 110-118
10. Ilany J, Bilan P J, Kapur S, Caldwell J S, Parti M E, Marette A, Kahn C R. Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level[J]. Proc Nat Acad Sci, 2006, 103(12): 4481-4486
11. Reynet C, Kahn C R. Rad: a member of the Ras family overexpressed in muscle of type II diabetic humans[J]. Science, 1993, 262(5138): 1441-1444
12. Nold J L, Georgieff M K. Infants of diabetic mothers[J]. Pediatr Clin North Am, 2004, 51(3): 619-637
13. Nelson C A, Wewerka S, Thomas K M, Tribby-Walbridge S, deRegnier R, Georgieff M. Neurocognitive sequelae of infants of diabetic mothers[J]. Behav Neurosci, 2000,114(5): 950-956
14. Hata K, Okano M, Lei H, Li E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice[J]. Develop, 2002, 129(8): 1983-1993
15. Okano M, Bell D W, Haber D A, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development[J]. Cell, 1999, 99(3): 247-257
16. Chen T P, Ueda Y, Dodge J E, Wang Z, Li E. Establishment and Maintenance of Genomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b[J]. Mol Cell Biol, 2003, 23(16): 5594-5605
17. Wentzel P, Wentzel C R, Gareskog M B, Wentzel P, Wentzel C R, Gareskog M B, Eriksson U J. Induction of embryonic dysmorphogenesis by high glucose concentration, disturbed inositol metabolism, and inhibited protein kinase C activity[J]. Teratology, 2001,63(5): 193-201
18. Reece EA, Ji I, Wu YK, Zhao Z. Characterization of differential gene expression profiles in diabetic embryopathy using DNA microarray analysis[J]. Am J Obstet Gynecol, 2006,195(4): 1075-1080
1. Beebe L F, Kaye P L. Maternal diabetes and retarded preimplantation development of mice[J]. Diabetes, 2001,40(4): 457-461
2. Diamond M P, Moley K H, Pellicer A, Vaughn W K, DeCherney A H. Effects of streptozotocin and alloxan-induced diabetes mellitus on mouse follicular and early embryo development[J]. J Reprod Fertil 1989, 86(1):1-10
3. De Hertogh R, Vanderheyden I, Pampfer S, Robin D, Dufrasne E, Delcourt J. Stimulatory and inhibitory effects of glucose and insulin on rat blastocyst development in vitro[J]. Diabetes, 1991, 40(5): 641-647
4. Mihalik J, Rehak P, Koppel J. The influence of insulin on the in vitro development of mouse and bovine embryos[J]. Physiol Res, 2000, 49(3): 347-354
5. Lea R G, Andrade L P, Rae M T, Hannah L T, Kyle C E, Murray J F, Rhind S M, Miller D W. Effects of maternal undernutrition during early pregnancy on apoptosis regulators in the ovine fetal ovary[J]. Reproduction, 2006,131(1): 113-124
6. Rehak P, Mihalik J, Vesela J, Cikos S, Baran V, Koppel J. Effects of impaired maternal insulin secretion on preimplantation embryo development in ICR mice[J]. Physiol Res, 1996, 45(6): 453-458
7. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
8 Reusens-Billen B, Remacle C, Daniline J, Hoet J J. Cell proliferation in pancreatic islets of rat fetuses and neonates from normal and diabetic mothers. An in vitro and in vivo study[J]. Horm Metab Res, 1984, 16(11): 565-571
9. Aerts L, Vercruysse L, Van Assche F A. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats[J]. Diabetes Res Clin Pract, 1997, 38(1): 9-19
10. Chang A S, Dale A N, Moley K H. Maternal diabetes adversely affects preovulatory oocyte maturation, development, and granulosa cell apoptosis[J]. Endocrinology, 2005,146(5): 2445-2453
11. Colton S A, Humpherson P G, Leese H J, Downs SM. Physiological changes in oocyte-cumulus cell complexes from diabetic mice that potentially influence meiotic regulation[J]. Biol Reprod, 2003, 69(3): 761-770
12. Colton S A, Pieper G M, Downs S M. Altered meiotic regulation in oocytes from diabetic mice[J]. Biol Reprod, 2002,67(1): 220-231
13.Vesela J,Cikos S,Hlinka D,Rehak P,Baran V,Koppel J.Effects of impaired insulin secretion on the fertilization of mouse oocytes[J].Hum Reprod,1995,10(12):3233-3236
14.Wi J K,Kim J K,Youn J H.Reduced glucose clearance as the major determinant of postabsorptive hyperglycemia in diabetic rats[J].Am J Physiol,1998,274(2 Pt 1):E257-E264
15.Scarano W R,Messias A G,Oliva S U,Klinefelter GR,Kempinas WG.Sexual behaviour,sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats[J].Int J Androl,2006,29(4):482-488
16.Soudamani S,Malini T,Balasubramanian K.Effects of streptozotocin-diabetes and insulin replacement on the epididymis of prepubertal rats:histological and histomorphometric studies[J].Endocr Res,2005,31(2):81-98
17 Soudamani S,Yuvaraj S,Malini T,Balasubramanian K.Experimental diabetes has adverse effects on the differentiation of ventral prostate during sexual maturation of rats[J].Anat Rec A Discov Mol Cell Evol Biol,2005,287(2):1281-1289
18.Hassan A A,Hassouna M M,Taketo T,Gagnon C,Elhilali M M.The effect of diabetes on sexual behavior and reproductive tract function in male rats[J].J Urol,1993,149(1):148-154
19.Balasubramanian K,Sivashanmugam P,Thameemdheen S,Govindarajulu P.Effect of diabetes mellitus on epididymal enzymes of adult rats[J].Indian J Exp Biol,1991,29(10):907-909
20.Cameron D F,Rountree J,Schultz R E,Repetta D,Murray F T.Sustained hyperglycemia results in testicular dysfunction and reduced fertility potential in BBWOR diabetic rats[J].Am J Physiol,1990,259(6 Pt 1):E881-E889
21.Seethalakshmi L,Menon M,Diamond D.The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat[J].J Urol,1987(1),138:190-194
22.孙丽霞,周丛乐,王红梅,等.母亲孕期糖尿病对子代脑发育影响的研究[J].中华围产医学杂志,2004,7(6):346-348
23.陈晓霞,周丛乐,王红梅,等.糖尿病母亲婴儿脑发育状况的研究[J].中华围产医学杂志,2005,8(5):300-303
24.Aerts L,Van Assche F A.Animal evidence for the transgenerational development of diabetes mellitus[J].Int J Biochem Cell B,2006,38(5-6):894-903
25.Harvey M B,Kaye P L.Insulin stimulates protein synthesis in compacted mouse embryos[J].Endocrinology,1988,122(3):1182-1184
26.Harvey M,Kaye P L.Insulin increases the cell number of the immer cell mass and stimulates morphological development of mouse blastocysts in vitro[J].Develop,1990,110(3):963-967
27.Kaye P L,Pemble L,Hobbs J G.Protein metabolism in preirnplantation mouse embryos[J].Prog Clin Biol Res, 1986, 217B: 103-106
28. Dunglison G F, Kaye P L. Insulin Regulates Protein Metabolism in Mouse Blastocysts[J]. Mol Reprod Dev, 1993, 36(1): 42-48
29. Martin-Gronert M S, Ozanne S E. Maternal nutrition during pregnancy and health of the offspring[J]. Biochem Soe T, 2006, 34(5): 779-782
30. Gerber R T, Holemans K, O'Brien-Coker I, Mallet A I, van Bree R, Van Assche F A, Poston L. Cholesterol-independent endothelial dysfunction in virgin and pregnant rats fed a diet high in saturated fat [J].J Physiol, 1999, 517(Pt 2): 607-616
31. Taylor P D, Khan I Y, Lakasing L, Dekou V, O'Brien-Coker I, Mallet A I, Hanson M A, Poston L. Uterine artery function in pregnant rats fed a diet supplemented with animal lard [J].Exp Physiol, 2003, 88(3): 389-398
32. Sasaki H, Ferguson-Smith A C, Shum A S, Barton S C, Surani M A. Temporal and spatial regulation of H19 imprinting in normal and uniparental mouse embryos[J]. Develop, 1995,121(12): 4195-4202
33. Doherty A S, Mann M R, Tremblay K D, Bartolomei M S, Schultz R M. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo[J]. Biol Reprod, 2000, 62(6): 1526-1535
34. Waterland R A, Lin J R, Smith C A, Jirtle R L. Post-weaning diet affects genomic imprinting at the insulin-like growth factor2 (Igf2) locus[J]. Hum Mol Genet, 2006,15(5): 705-716
35. Weber M, Hagege H, Murrell A, Brunei C, Reik W, Cathala G, Forne T. Genomic imprinting controls matrix attachment regions in the Igf2 gene[J]. Mol Cell Biol, 2003, 23(24): 8953-8959
36. Kobayashi H, Suda C, Abe T, Kohara Y, Ikemura T, Sasaki H. Bisulfite sequencing and dinucleotide content analysis of 15 imprinted mouse differentially methylated regions (DMRs): paternally methylated DMRs contain less CpGs than maternally methylated DMRs[J]. Cytogenet Genome Res, 2006, 113(1-4): 130-137
37. Reik W, Dean W. DNA methylation and mammalian epigenetics[J]. Electrophoresis, 2001, 22(14): 2838-4283
38. Gebert C, Wrenzycki C, Herrmann D, Groger D, Reinhardt R, Hajkova P, Lucas-Hahn A, Carnwath J, Lehrach H, Niemann H. The bovine IGF2 gene is differentially methylated in oocyte and sperm DNA[J]. Genomics, 2006, 88(2): 222-229
39. Serman A, Vlahovic M, Serman L, Bulic-Jakus F. DNA Methylation as a regulatory mechanism for gene expression in mammals[J]. Coll Antropol, 2006,30(3):665-671
40. Warnecke P M, Mann J R, Frommer M, Clark S J. Bisulfite Sequencing in Preimplantation Embryos: DNA Methylation Profile of the Upstream Region of the Mouse Imprinted H19 Gene[J]. Genomics, 1998,51(2): 182-190
41. Chen T, Ueda Y, Dodge J E, Wang Z, Li E. Establishment and Maintenance of Genomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b[J]. Mol Cell Biol, 2003, 23(16): 5594-5605
42. Okano M, Bell D W, Haber D A, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development[J]. Cell, 1999, 99(3): 247-257
43. Hata K, Okano M, Lei H, Li E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice[J]. Develop, 2002, 129(8): 1983-1993
44. Ilany J, Bilan PJ, Kapur S, Caldwell J S, Patti M E, Marette A, Kahn C R. Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level[J]. Proc Nat Acad Sci, 2006, 103(12): 4481-4486
45. Reynet C, Kahn C R. Rad: a member of the Ras family overexpressed in muscle of type II diabetic humans[J]. Science, 1993, 262(5138): 1441-1444
2. Plagemann A, Harder T, Franke K, Kohlhoff R. Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers[J]. Diabetes Care, 2002,25(1): 16-22
3. Reusens B, Remacle C. Programming of the endocrine pancreas by the early nutritional environment[J]. Int Biochem Cell B, 2006, 38(5-6): 913-922
4. Martin-Gronert M S, Ozanne S E. Programming of appetite and type 2 diabetes[J]. Early Hum Dev, 2005, 81(12): 981-988
5. Fernandez-Twinn D S, Ozanne S E. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome[J]. Physiol Behav, 2006, 88(3): 234-243
6. Ravelli A C, van der Meulen J H, Michels R P, Osmond C, Barker D J, Hales C N, Bleker O P. Glucose tolerance in adults after prenatal exposure to famine[J]. Lancet, 1998, 351(9097): 173-177
7. Barker D J, Hales C N, Fall C H, Osmond C, Phipps K, Clark P M. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia, 1993,36(1 ):62-67
8. Bennett F, Watson-Brown C, Thame M, Wilks R, Osmond C, Hales N, Barker D, Forrester T. Shortness at birth is associated with insulin resistance in pre-pubertal Jamaican children[J]. Eur J Clin Nutr, 2002, 56(6): 506-511
9. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J]. Diabet Med, 1998, 15(8): 688-694
10. Plagemann A, Harder T, Kohlhoff R, Fahrenkrog S, Rodekamp E, Franke K, Dudenhausen J W. Impact of early neonatal breast-feeding on psychomotor and neuropsychological development in children of diabetic mothers [J]. Diabetes Care, 2005, 28(3): 573-578
11. McCance R A. Food growth and time [J]. Lancet, 1962, 2: 271-272
12. Hahn P. Effect of litter size on plasma cholesterol and insulin and some liver and adipose tissue enzymes in adult rodents[J]. J Nutr, 1984, 114(7): 1231-1234
13. Young J B. Effects of litter size on sympathetic activity in young adult rats[J]. Am J Physiol Regul Integr Comp Physiol, 2002, 282: R1113-R1121
14. Holmes J M, Duffner L A. The effect of litter size on normal retinal vascular development in the neonatal rat[J]. Curr Eye Res, 1995, 14(8): 737-740
15. Koldovsky O, Hahn P, Hromadova M, Krecek J, Macho L. Late effects of early nutritional manipulations[J]. Physiol Res, 1995,44(6):357-360
16. Langley S C, Browne R F, Jackson A A. Altered glucose tolerance in rats exposed to maternal low protein diets in utero[J]. Comp Biochem Physiol, 1994, 109(2): 223-229
17. Langley S C, Jackson A A. Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets[J]. Clinical Science, 1994, 86(2): 217-222
18. Langley-Evans S C. Critical difference between two low protein diet protocols in the programming of hypertension in the rat[J]. Int J Food Sci Nutr, 2000, 51(1): 11-17
19. Kwong W Y, Wild A E, Roberts P, Willis A C, Fleming T P. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension[J]. Development, 2000, 127(19): 4195-4202
20. Petrie L, Duthie S J, Rees W D, McConnell J M. Serum concentrations of homocysteine are elevated during early pregnancy in rodent models of fetal programming[J]. Br J Nutr, 2002, 88(5): 471-477
21. Kind K L, Clifton P M, Grant P A, Owens P C, Sohlstrom A, Roberts C T, Robinson J S, Owens J A. Effect of maternal feed restriction during pregnancy on glucose tolerance in the adult guinea pig[J]. Am J Physiol Regul Integr Comp Physiol, 2003, 284(1): R140-R152
22. Kind K L, Clifton P M, Katsman A I, Tsiounis M, Robinson J S, Owens J A. Restricted fetal growth and the response to dietary cholesterol in the guinea pig[J]. Am J Physiol, 1999, 277(6Pt2): R1675-R1682
23. Garofano A, Czernichow P, Breant B. In utero undernutrition impairs rat beta-cell development [J]. Diabetologia, 1997,40(10): 1231-1234
24. Molendi-Coste O, Grumolato L, Laborie C, Lesage J, Maubert E, Ghzili H, Vaudry H, Anouar Y, Breton C, Vieau D. Maternal perinatal undernutrition alters neuronal and neuroendocrine differentiation in the rat adrenal medulla at weaning[J]. Endocrinology, 2006, 147(6): 3050-3059
25. Lesage J, Dufourny L, Laborie C, Bernet F, Blondeau B, Avril I, Breant B, Dupouy J P. Perinatal malnutrition programs sympathoadrenal and hypothalamic-pituitary-adrenal axis responsiveness to restraint stress in adult male rats[J]. J Neuroendocrinol, 2002, 14(2): 135-143
26. Bieswal F, Ahn M T, Reusens B, Holvoet P, Raes M, Rees W D, Remacle C. The importance of catch-up growth after early malnutrition for the programming of obesity in male rat. Obesity (Silver Spring), 2006,14(8): 1330-1343
27. Vickers M H, Breier B H, Cutfield W S, Hofman P L, Gluckman P D. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition[J]. Am J Physiol Endocrinol Metab, 2000, 279(1): E83-E87
28. Mericq V. Low birth weight and endocrine dysfunction in postnatal life[J]. Pediatr Endocrinol Rev, 2006, 4(1): 3-14
29. Blondeau B, Avril I, Duchene B, Breant B. Endocrine pancreas development is altered in foetuses from rats previously showing intrauterine growth retardation in response to malnutrition[J]. Diabetologia, 2002,45(3): 394-401
30. Kanitz E, Tuchscherer M, Puppe B, Tuchscherer A, Stabenow B. Consequences of repeated early isolation in domestic piglets (Sus scrofa) on their behavioural, neuroendocrine, and immunological responses[J]. Brain Behav Immun, 2004, 18(1): 35-45
31. Canlon B, Li H, Olson L, Hultcrantz M, Borg E. Stage dependent development of intraocular cochlear grafts[J]. Hear Res, 1992, 64(1): 142-148
32. De Blasio M J, Gatford K L, McMillen I C, Robinson J S, Owens J A. Placental restriction of fetal growth increases insulin action, growth, and adiposity in the young lamb[J]. Endocrinology, 2007, 148(3): 1350-1358
33. Bakker J M, Schmidt E D, Kroes H, Kavelaars A, Heijnen C J, Tilders F J, van Rees E P. Effects of short-term dexamethasone treatment during pregnancy on the development of the immune system and the hypothalamo-pituitary adrenal axis in the rat[J]. J Neuroimmunol, 1995, 63(2): 183-191
34. Wu G, Bazer F W, Cudd T A, Meininger C J, Spencer T E. Maternal Nutrition and Fetal Developmen[J]. J Nutr, 2004, 134(9): 2169-2172
35. Petry C J, Ozanne S E, Hales C N. Programming of intermediary metabolism[J]. Mol Cell Endocrinol, 2001, 185(1-2): 81-91
36. Hales C N, Barker D J. Type 2 (non-insulin-dependant) diabetes mellitus: the thrifty phenotype hypothesis[J]. Diabetologia, 1992, 35(7): 595-601
37. Wells J C. The thrifty phenotype hypothesis: thrifty offspring or thrifty mother?[J]. Theor Biol, 2003, 221(1): 143-161
38. Oliver M H, Harding J E, Breier B H, Gluckman PD. Fetal insulin - like growth factor (IGF) - I and IGF - II are regulated differently by glucose and insulin in the sheep fetus [J]. Reprod Ferti Dev, 1996, 8(1): 167-172
39. Fowden A L, Hill D J. Intra-uterine programming of the endocrine pancreas. [J]Br Med Bull, 2001, 60: 123-142
40. Feil R. Environmental and nutritional effects on the epigenetic regulation of genes[J]. Mutat Res, 2006; 600(1-2): 46-57
41. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic[J]. Diabetes, 2005, 54(7): 1899-1906
42. Waterland R A, GarzaC. Potential mechanisms of metabolic imprinting that lead to chronic disease[J]. Am J Clin Nutr, 1999, 69(2): 179-197
43. Dolinoy D C, Weidman J R, Waterland R A, Jirtle RL. Maternal genistein alters coat color and protects A~(vy) mouse offspring from obesity by modifying the fetal epigenome[J]. Environ Health Perspect, 2006, 114(4): 567-572
1.Reusens B,Remacle C.Programming of the endocrine pancreas by the early nutritional environment[J].Int Biochem Cell B,2006,38(5-6):913-922
2.Byrne C D.Programming other hormones that affect insulin[J].Br Med Bull.,2001,60:153-171
3.Doherty A S,Temeles G L,Schultz R M.Temporal pattern of IGF-Ⅰ expression during mouse preimplantation embryogenesis[J].Mol Reprod Dev,1994,37(1):21-26
4.Harvey M,Kaye P L.Insulin increases the cell number of the immer cell mass and stimulates morphological development of mouse blastocysts in vitro[J].Develop,1990,110(3):963-967
5.Harvey M B,Kaye P L.Insulin stimulates protein synthesis in compacted mouse embryos[J].Endocrinology,1988,122(3):1182-1184
6.Tsai H D,Chang C C,Hsieh Y Y.Recombinant human leukemia inhibitory factor enhances the development of preimplantation mouse embryo in vitro[J].J Assist Reprod Genet,2000,17(6):352-355
7.Gardner H G,Kaye P L.Insulin increase cell numbers and morphological development in mouse pre-implantation embryos in vitro[J].Reprod Fertil Dev,1991,3(1):79-91
8.Kaye P L,Pemble L,Hobbs J G.Protein metabolism in preimplantation mouse embryos[J].Prog Clin Biol Res,1986,217B:103-106
9.Dunglison G F,Kaye P L.Insulin Regulates Protein Metabolism in Mouse Blastocysts[J].Mol Reprod Dev,1993,36(1):42-48
10.Draznin B,Solomons C C,Emler C A,Schalch D S,Sussman K E.Decreased insulin binding and degradation associated with depressed intracellular ATP content[J].Diabetes,1980,29(3):221-226
11.Draznin B.Molecular mechanisms of insulin resistance:serine phosphorylation of insulin receptor substrate-1 and increased expression of p85alpha:the two sides of a coin[J].Diabetes 2006,55(8):2392-7239
12.白照岱,刘凯,邴鲁军.胰岛素对小鼠早期胚胎体外发育的影响[J]生殖医学杂志,2004,13(5):286-290
13.Puscheck E E,Pergament E,Patel Y,Dreschler J,Rappolee D A.Insulin receptor substrate-1 is expressed at high levels in all cells of the peri-implantation mouse embryo[J].Mol Reprod Dev 1998,49(4):386-393
14.Bonner-Weir S.Perspective:postnatal pancreatic β cell growth endocrinology[J].Endocrinology,2000;141(6):1926-1929
15.Martin-Gronert M S,Ozanne S E.Programming of appetite and type 2 diabetes[J].Early Human Development, 2005, 81(12): 981-988
16. Pampfer S, de Hertogh R, Vanderheyden I, Michiels B, Vercheval M. Decreased inner cell mass proportion in blastocysts from diabetic rats[J]. Diabetes, 1990,39(4): 471-476
17. Beebe L F, Kaye P L. Maternal diabetes and retarded preimplantation development of mice[J]. Diabetes, 1991, 40(4): 457-461
18. Diamond M P, Moley K H, Pellicer A, Vaughn W K, DeCherney AH. Effects of streptozotocin- and alloxan-induced diabetes mellitus on mouse follicular and early embryo development[J]. J Reprod Fertil, 1989, 86(1): 1-10
19. De Hertogh R, Vanderheyden I, Pampfer S, Robin D, Dufrasne E, Delcourt J. Stimulatory and inhibitory effects of glucose and insulin on rat blastocyst development in vitro[J]. Diabetes, 1991, 40(5): 641-647
20. Mihalik J, Rehak P, Koppel J. The influence of insulin on the in vitro development of mouse and bovine embryos[J]. Physiol Res, 2000,49(3): 347-354
21. Plagemann A, Harder T, Franke K, Kohlhoff R. Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers[J]. Diabetes Care, 2002, 25(1): 16-22
22. Fernandez-Twinn D S, Ozanne S E, Ekizoglou S, Doherty C, James L, Gusterson B, Hales C N. The maternal endocrine environment in the low-protein model of intra-uterine growth restriction[J]. Br J Nutr, 2003, 90(4): 815-822
23. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
24. Verhaeghe J, Van Bree R, Van Herck, Laureys J, Bouillon R, Van Assche F A. C-peptide, insulin-like growth factors I and II, and insulin-like growth factor binding protein-I and II, and insulin-like growth factor binding protein-I in umbilical cord serum: Correlations with birth weight[J]. Am J Obstet Gynecol, 1993, 169(1): 89-97
25. Wiznitzer A, Reece E A, Homko C, Furman B, Mazor M, Levy J. Insulin-like growth factors, their binding proteins, and fetal macrosomia in offspring of nondiabetic pregnant women[J]. Am J Perinat, 1998, 15(1): 23-28.
26. Pedersen J. The Pregnant, Diabetic and Her Newborn.Problems and Management[M], 1997,Williams and Wilkins, Baltimore, MD, USA
27. Freinkel N. Banting Lecture 1980.Of pregnancy and progeny[J]. Diabetes, 1980,29(12):1023-1035
28. Van Assche F A, Holemans K, Aerts L. Fetal growth and consequences for later life[J]. J Perinat Med, 1998, 26(5): 337-346
29. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
30. Hamman R F. Genetic and environment determinants of non-insulin dependent diabetes mellitus[J]. Diabetes Metab Rev, 1992, 8(4):287-338
31. Martin A O, Simpson J L, Ober C, Freinkel N. Frequency of diabetes mellitus in mothers of probands with gestational diabetes, possible maternal influence on the predisposition to gestational diabetes[J]. Am J Obstet Gynecol. 1985, 151(4): 471-475
32. Dorner G, Steindel E, Thoelke H, Schliack V. Evidence for decreasing prevalence of diabetes mellitus in childhood apparently produced by prevention of hyperinsulinism in the foetus and newborn[J]. Exp Clin Endocr Diab, 1984, 84(2): 134-142
33. Dorner G, Plagemann A, Reinagel H. Familial diabetes aggregation in type 2 diabetics, gestational diabetes as apparent risk factor for increased diabetes susceptibility in the offspring[J]. Exp Clin Endocr Diab, 1987, 89(1): 84-90
34. Saini KS, Thompson C, Winterford C M, Walker N I, Cameron D P. Streptozotocin at low doses induces apoptosis and at high doses causes necrosis in a murine[J]. Biochem.Mol.Biol.Int, 1996, 39(6): 1229-1236
35. Ito M, Kondo Y, Nakatani A, Hayashi K, Naruse A. Characterization of low dose streptozotocin-induced progressive diabetes in mice[J]. Environ Toxicol Phar, 2001, 9(3): 173-184
36. Kervran A, Guillaume M, Jost A. The endocrine pancreas of the fetus from diabetic pregnant rat[J]. Diabetologia, 1978, 15(5): 387-393
37. Aerts L, Van Bree R, Feytons V, Rombauts W, Van Assche FA.Plasma amino acids in diabetic pregnant rats and in their fetal and adult offspring[J]. Biol Neonate, 1989, 56(1): 31-39
38. Gauguier D, Bihoreau M T, Picon L, Ktorza A. Insulin secretion in adult rats after intrauterine exposure to mild hyperglycemia during late gestation[J]. Diabetes, 1991,40 Suppl 2:109-114
39. Philipps A F, Rosenkrantz T S, Grunnet M L, Connolly M E, Porte P J, Raye J R. Effects of fetal insulin secretory deficiency on metabolism in fetal lamb[J]. Diabetes, 1986,35(9):964-72
40. Schroeder R E, Doria-medina C L, Das U G, Sivitz W I, Devaskar S U. Effect of maternal diabetes upon fetal rat myocardial and skeletal muscle glucose transporters[J]. Pediatr Res, 1997, 41(1):11-19
41. Canavan J P, Goldspink D F. Maternal diabetes in rats II. Effects on fetal growth and protein turnover[J]. Diabetes, 1988,37(12): 1671-1677
42. Holemans K, Aerts L, Van Assche F A. Evidence for an insulin resistance in the adult offspring of streptozotocin-diabetic pregnant rats[J]. Diabetologia, 1991, 34(2): 81-85
43. Holemans K, Aerts L, Van Assche F A. Absence of pregnancy-induced alterations in tissue insulin sensitivity in the offspring of diabetic rats[J]. J Endocrinol, 1991,131(3): 387-393.
44. Boujendar S, Reusens B, Merezak S, Ann M T, Arany E, Hill D, Remacle C. Taurine supplementation to a low protein diet during fetal and early postnatal life restores a normal proliferation and apoptosis of rat pancreatic islets[J]. Diabetologia, 2002, 45(6): 856-866
45. Petrik J, Reusens B, Arany E, Remacle C, Coelho C, Hoet J J, Hill D J. A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor II[J]. Endocrinology, 1999, 140(10): 4861-4873
46. Snoeck A, Remacle C, Reusens B, Hoet J J.Effect of low protein diet during pregnancy on the fetal rat endocrine pancreas[J]. Biol Neonate, 1990, 57(2): 107-118
47. Cherif H, Reusens B, Dahri S, Remacle C. A protein restricted diet during pregnancy alters in vitro insulin secretion from islets of fetal Wistar rats[J]. J Nutr, 2001, 131(5), 1551-1559
48. Blondeau B, Lesage J, Czernichow P, Dupouy J P, Breant B. Glucocorticoids impair fetal β cell development in rat[J].Am J Phys, 2001, 281(3), E592-E599
49. Garofano A, Czernichow P, Breant B. In utero undernutrition impairs rat β-cell development[J]. Diabetologia, 1997, 40(10), 1231-1234
50. Garofano A, Czernichow P, Breant B. Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat[J]. Diabetologia, 1998, 41(9): 1114-1120
1.Feil R.Environmental and nutritional effects on the epigenetic regulation of genes[J].Mutat Res,2006,600(1-2):46-57
2.Walter J,Paulsen M.Imprinting and disease[J].Semin Cell Dev Biol,2003,14(1):101-110
3.McGrath J,Solter D.Completion of mouse embryogenesis requires both the maternal and paternal genomes[J].Cell,1984,37(1):179-183
4.Surani M A H,Barton S C,Norris M L.Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis[J].Nature,1984,308(5959):548-550
5.李宏军,郭应禄,张志文.印迹基因及其对胚胎发育的调控[J].生物化学与生物物理进展,1999,26(1):19-22
6.Hajkova P,Erhardt S,Lane N,Haaf T,E1-Maarri O,Reik W,Walter J,Surani M A.Epigenetic reprogramming in mouse primordial germ cells[J].Mech Dev,2002,117(1-2):15-23
7.Barlow D P.Gametic imprinting in mammals[J].Science,1995,270(5242):1610-1613
8.Wrenzycki C,De Sousa P,Overstrom E W,Duby R T,Herrmann D,Watson A J,Niemann H,O'Callaghan D,Boland M P.Effects of superovulated heifer diet type and quantity on relative mRNA abundances and pyruvate metabolism in recovered embryos[J].J.Reprod.Fertil,2000,118(1):69-78
9.Thompson SL,Konfortova G,Gregory R I,Reik W,Dean W,Feil R.Environmental effects on genomic imprinting in mammals[J].Toxicol Lett,2001,120(1-3):143-150
10.Holm P,Walker S K,Seamark R F.Embryo viability,duration of gestation and birth weight in sheep after transfer of in vitro matured and in vitro fertilized zygotes cultured in vitro or in vivo[J].J Reprod Fertil,1996,107(2):175-181
11.Young L E,Sinclair K D,Wilmut I.Large offspring syndrome in cattle and sheep[J].Rev Reprod,1998,3(3):155-163.
12.Khosla S,Dean W,Brown D,Reik W,Feil R.Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes[J].Biol Reprod,2001,64(3):918-926
13.Sinclair K D,Young L E,Wilmut I,McEvoy T G In utero overgrowth in ruminants following embryo culture:Lessons from mice and a warning to men[J].Hum Reprod,2000,15,Supplement 5:68-86
14.李云龙,刘春巧主编著.动物发育生物学[M].山东科学技术出版,2003,549-561
15.Pteifer K,Tilghman S M.Allele-specific gene expression in mammals:the curious case of the imprinted RNAs[J].Genes Dev,1994,8(16):1867-1874
16.Bartolomei M S,Zemel S,Tilghman S M.Parental imprinting of the mouse H19 gene[J].Nature,1991,351(6322):153-155
17.DeChiara T M,Robertson E J,Efstratiadis A.Parental imprinting of the mouse insulin-like growth factor Ⅱ gene[J].Cell,1991,64(4):849-859
18.Villar A J,Eddy E M,Pedersen R A.Developmental regulation of genomic imprinting during gametogenesis[J],Dev Biol,1995,172(1):264-271
19.Weber M,Milligan L,Delalbre A,Antoine E,Brunel C,Cathala G,Forne T.Extensive tissue-specific variation of allelic methylation in the Igf2 gene during mouse fetal development:relation to expression and imprinting[J].Mech Develop,2001,101(1-2):133-141
20.Doherty A S,Mann M R,Tremblay K D,Bartolomei M S,Schultz R M.Differential Effects of Culture on Imprinted H19 Expression in the Preimplantation Mouse Embryo[J].Biol Reprod,2000,62(6),1526-1535
21.Maher E R,Reik W.Beckwith-Wiedemann syndrome:imprinting in clusters revisited[J].J Clin Invest,2000,105(3):247-252
22.Eggenschwiler J,Ludwig T,Fisher P,Leighton P A,Tilghman S M,Efstratiadis A.Mouse mutant embryos overexpressing IGF-Ⅱ exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes[J].Genes Dev,1997,11(23):3128-3142
23.Reik W,Bowden L,Constancia M,Dean W,Fell R,Forne T,Kelsey G,Maher E,Moore T,Sun F L,Walter J.Regulation of Igf2 imprinting in development and disease[J].Int J Dev Biol,1996,Suppl 1:53S-54S
24.Jirtle R L,Sander M,Barrett J C.Genomic imprinting and environmental disease susceptibility[J].Environ Health Perspect,2000,108(3):271-278
25.杨玉华,何小兵.印迹基因IGF2和H19的研究进展[J].国外医学分子生物学分册,2002,24(4):254-256
26.Kwong W Y,Miller D J,Ursell E,Wild A E,Wilkins A P,Osmond C,Anthony F W,Fleming T P.Imprinted gene expression in the rat embryo-fetal axis is altered in response to periconceptional maternal low protein diet[J].Reproduction,2006,132(2):265-277
27.Howell C Y,Bestor T H,Ding F,Latham K E,Mertineit C,Trasler J M,Chaillet J R.Genomic imprinting disrupted by a maternal effect mutation in the Dnmtl gene[J].Cell,2001,104(6):829-838
28.Li E,Beard C,Jaenisch R.Role for DNA methylation in genomic imprinting[J].Nature,1993,366(6453):362-365
1.Feil R.Environmental and nutritional effects on the epigenetic regulation of genes[J].Mutat Res 2006,600(1-2):46-57.
2.Razin A,Shemer R.DNA methylation in early development[J].Hum Mol Genet,1995,4 Spec No:1751-1755
3.John R M,Surani M A.Imprinted genes and regulation of gene expression by epigenetic inheritance[J].Curr Opin Cell Biol,1996,8(3):348-353
4.Dolinoy D C,Weidman J R.,Jirtle R L.Epigenetic gene regulation:Linking early developmental environment to adult disease[J].Reprod Toxicol,2007,23(3):297-307
5.Constancia M,Pickard B,Kelsey G,Reik W.Imprinting mechanisms[J].Genome Res,1998,8(9):881-900
6.Tilghman S M.The sins of the fathers and mothers:genomic imprinting in mammalian development [J].Cell,1999,96:185-193
7.Jaenisch R,Bird A.Epigenetic regulation of gene expression:how the genome integrates intrinsic and environmental signals[J].Nat Genet,2003,33 Suppl:245-254
8.Chaillet J R,Vogt T F,Beier D R,Leder P.Parental-specific methylation of an imprinted transgene is established during gametogenesis and progressively changes during embryogenesis[J].Cell,1991,6(1):77-83
9.Chaillet J R,Bader D S,Leder P.Regulation of genomic imprinting by gametic and embryonic processes[J].Genes Dev,1995,9(10):1177-1187
10.Hajkova P,Erhardt S,Lane N,Haaf T,EI-Maarri O,Reik W,Walter J,Surani MA.Epigenetic reprogramming in mouse primordial germ cells[J].Mech Dev,2002,117(1-2):15-23
11.Kay G F,Penny G D,Patel D,Ashworth A,Brockdorff N,Rastan S.Expression of Xist during Mouse Development Suggests a Role in the Initiation of X Chromosome Inactivation[J].Cell,1993,72(2):171-182
12.岳占碰,杨增明.哺乳动物基因印迹及其与胚胎发育的关系[J],动物学杂志,1999,34(4):56-59
13.Schoenherr C J,Levorse J M,Tilghman S M.CTCF maintains differential methylation at the Igf2/H19 locus[J].Nat Genet,2003,33(1):66-69
14.Fedoriw A M,Stein P,Svoboda P,Schultz RM,Bartolomei MS.Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting[J].Science,2004,303(5655):238-240
15.Bell A C,Felsenfeld G.Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene[J].Nature,2000,405(6785):482-485
16.Hark A T,Schoenherr C J,Katz D J,Ingrain RS,Levorse JM,Tilghman SM.CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus[J].Nature,2000,405(6785):486-489
17.程姗.印记控制区(ICR)的调控机制[J].生命的化学,2004,24(5):383-386
18.Walter J,Paulsen M.Imprinting and disease[J].Semin Cell Dev Biol,2003,14(1):101-110
19.尹斌,沈岩.DNA的甲基化修饰与DNA甲基转移酶[J].国外医学遗传学分册,2001,24(1):5-8
20.Hata K,Okano M,Lei H,Li E.Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice[J].Develop,2002,129(8):1983-1993
21.Yoder J A,Soman N S,Verdine G L,Bestor TH.DNA(cytosine-5)-methyltransferases in mouse cells and tissues.Studies with a mechanism-based probe[J].J Mol Biol,1997,270(3):385-395
22.Okano M,Bell D W,Haber D A,Li E.DNA methyltransferases Dnmt3a and Drtmt3b are essential for de novo methylation and mammalian development[J].Cell,1999(3),99:247-257
23.Bourc'his D,Xu GL,Lin CS,Bollman B,Bestor TH.Dnmt3L and the establishment of maternal genomic imprints[J].Science,2001,294(5551):2536-2539
24.Kaneda M,Okano M,Hata K,Sado T,Tsujimoto N,Li E,Sasaki H.Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting[J].Nature,2004,429(6994):900-903
25.Li E,Beard C,Jaenisch R.The Role of DNA Methylation in Genomic Imprinting[J].Nature,1993,366(6453):362-365
26.Leighton P A,Ingram R S,Eggenschwiler J,Efstratiadis A,Tilghman SM.Disruption of Imprinting Caused by Deletion of the H19 Gene Region in Mice[J].Nature,1995,375(6526):34-39
27.Barlow D P.Gametic Imprinting in Mammals[J].Science,1995,270(5242):1610-1613
28.Vassena R,Dee Schramm R,Latham K E.Species-dependent expression patterns of DNA methyltransferase genes in mammalian oocytes and preimplantation embryos[J].Mol Reprod Dev,2005,72(4):430-436
29.Chen T,Ueda Y,Dodge JE,Wang Z,Li E.Establishment and Maintenance ofGenomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b[J].Mol Cell Biol,2003,23(16):5594-5605
30.LeGouy E,Thompson E M,Muehardt C,Renard JP.Differential preimplantation regulation of two mouse homologues of the yeast SWI2 protein[J].Dev Dyn,1998,212(1):38-48
31.Voncken J W,Schweizer D,Aagaard L,Sattler L,Jantsch MF,van Lohuizen M. Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status[J].J Cell Sci,1999,112(Pt 24):4627-4639
32.Robertson G T,Reisenauer A,Wright R,Jensen RB,Jensen A,Shapiro L,Roop RM.The Brucella abortus CcrM DNA methyltransferase is essential for viability,and its overexpression attenuates intracellular replication in murine macrophages[J].J Bacteriol,2000,182(12):3482-3489
33.赵冬梅.DNA甲基转移酶与早期胚胎发育[J].浙江大学学报(医学版),2005,34(3):281-284
34.Dolinoy D C,Weidman J R,Jirtle R L.Epigenetic gene regulation:Linking early developmental environment to adult disease[J].Reprod Toxicol,2007,23(3):297-307.
35.Thompson S L,Konfortova G,Gregory R I,Reik W,Dean W,Feil R.Environmental effects on genomic imprinting in mammals[J].Toxicol Lett,2001,120(1-3):143-150
36.Khosla S,Dean W,Brown D,Reik W,Feil R.Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes[J].Biol Reprod,2001,64(3):918-926
37.Sasaki H,Ishihara K,Kato R.Mechanisms of Igf2/H19 imprinting:DNA methylation,chromatin and long-distance gene regulation[J].J.Biochem.(Tokyo),2005,127(5):711-715
38.Doherty AS,Mann MR,Tremblay KD,Bartolomei MS,Schultz RM.Differential Effects of Culture on Imprinted H19 Expression in the Preimplantation Mouse Embryo[J].Biol Reprod,2000,62(6):1526-1535
39.Ungaro P,Casola S,Vernucci M,Pedone PV,Bruni CB,Riccio A.Relaxation of insulin-like growth factor-2 imprinting in rat cultured cells[J].Mol Cell Endocrinol,1997,135(2):153-163
40.Waterland R A,Dolinoy D C,Lin J R,Smith CA,Shi X,Tahiliani KG.Maternal methyl supplements increase offspring DNA methylation at Axin Fused[J].Genesis,2006,44(9):401-406
41.Dolinoy D C,Weidman J R,Waterland R A,Jirtle RL.Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome[J].Environ Health Perspect,2006,114(4):567-572
42.Okoji R S,Yu R C,Maronpot R R,Froines JR.Sodium arsenite administration via drinking water increases genome-wide and Ha-ras DNA hypomethylation in methyl-deficient C57BL/6J mice[J].Carcinogenesis,2002,23(5):777-85
43.Wu Q,Ohsako S,Ishimura R,Suzuki JS,Tohyama C.Exposure of Mouse Preimplantation Embryos to 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) Alters the Methylation Status of Imprinted Genes H19 and Igf2[J].Biol Reprod,2004,70(6):1790-1797
44.Weaver I,Champagne F A,Brown S,Dymov S,Sharma S,Meaney MJ,Szyf M.Reversal of maternal programming of stress responses in adult offspring through methyl supplementation[J].J Neurosci,2005,25(47):11045-11054
45.Zhu B,Huang X,Chen J,Lu Y,Chen Y,Zhao J.Methylation changes of H19 gene in sperms of X-irradiated mouse and maintenance in offspring[J].Biochem and Biophy Res Commu,2006,340(1):83-89
46.Koturbash I,Baker M,Loree J,Kutanzi K,Hudson D,Pogribny I,Sedelnikova O,Bonner W,Kovalchuk O.Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo[J].Int J Radiat Oncol Biol Phys,2006,66(2):327-330
47.范保星.DNA甲基化检测方法[J].国外医学遗传学分册,2002,25(2):99-101
48.黄琼晓,金帆,黄荷凤.DNA甲基化的研究方法学[J].国外医学遗传学分册,2004,27(6):354-358
49.Wan Y,Wang Y,Luo J,Lu Z.Bisulfite modification of immobilized DNAs for methylation detection[J].Biosens Bioelectron,2007,22(11):2415-2421
50.Fraga MF,Esteller M.DNA methylation:a profile of methods and applications[J].Biotechniques,2002,33(3):632-649
1.Dufrane D,van Steenberghe M,Guiot Y,Goebbels RM,Saliez A,Gianello P.Streptozotocin-induced diabetes in large animals(pigs/primates):role of GLUT2 transporter and beta-cell plasticity 1998[J].Transplantation,2006,81(1):36-45
2.Gajdosik A,Gajdosikova A,Stefek M,Navarova.J,Hozova R.Streptozotocin-induced experimental diabetes in male Wistar rats[J].Gen Physiol Biophys,1999,18(Spec No):54-62
3.Harlan D M,Barnett M A,Abe R,Pechhold K,Patterson NB,Gray GS,June CH.Very-low-dose streptozotocin induces diabetes in insulin promoter-mB7-1 transgenic mice[J].Diabetes,1995,44(7):816-823
4.Richens E R,Behbehani K.The effect of adjuvants on immune function in the multi-low-dose streptozotocin model ofmurine diabetes[J].Int J Tissue React,1988,10(4):207-216
5.Noguchi S,Ohba Y,Oka T.Involvement of epidermal growth factor deficiency in pathogenesis of oligozoospermia in streptozotocin-induced diabetic mice[J].Endocrinology,1990,127(5):2136-2140
6.Diamond M P,Moley K H,Pellicer A,Vaughn WK,DeCherney AH.Effects of streptozotocin- and alloxan-induced diabetes mellitus on mouse follicular and early embryo development[J],J Reprod Fertil,1989,86(1):1-10
7.耿娅,纪丽曼,周兴军,等.链脲佐菌素致迟发型大鼠1型糖尿病模型的研究[J].河北医药,2006,28(10):906-907
8.宋立江,蒋东升,郭金铭,等.小鼠腹腔注射链脲佐菌素高血糖模型实验观察[J].中国卫生检验杂志,2006,16(10):1257-1258
9.杨巍,罗春元,于春雷,等.不同剂量STZ诱导小鼠糖尿病模型的发病机制[J].吉林大学学报(医学版),2006,32(3):432-435
10.梁海荣,唐焕文,罗皓,等.链脲佐菌素诱导糖尿病大鼠肾病模型的建立应用[J].预防医学,2006,12(3):133-135
11.Ito M,Kondo Y,Nakatani A,Hayashi K,Naruse A..Characterization of low dose streptozotocin-induced progressive diabetes in mice[J].Environ Toxicol Phar,2001,9(3):173-184
12.Aerts L,Holemans K,Van Assche F A.Maternal diabetes during pregnancy:consequences for the offspring[J].Diabetes Metab Rev,1990,6(3):147-167
13.Reusens-Billen B,Remacle C,Daniline J,Hoet JJ.Cell proliferation in pancreatic islets of rat fetuses and neonates from normal and diabetic mothers.An in vitro and in vivo study[J].Horm Metab Res,1984,16(11):565-571
14. Aerts L, Vercruysse L, Van Assche F A. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats[J]. Diabetes Res Clin Pract, 1997,38(1): 9-19
15. Scarano W R, Messias A G, Oliva S U, Klinefelter GR, Kempinas WG. Sexual behaviour, sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats[J]. Int J Androl, 2006, 29(4): 482-488
16. Soudamani S, Malini T, Balasubramanian K. Effects of streptozotocin-diabetes and insulin replacement on the epididymis of prepubertal rats: histological and histomorphometric studies[J]. Endocr Res, 2005, 31(2): 81-98
17. Soudamani S, Yuvaraj S, Malini T, Balasubramanian K. Experimental diabetes has adverse effects on the differentiation of ventral prostate during sexual maturation of rats[J]. Anat Rec A Discov Mol Cell Evol Biol, 2005, 287(2): 1281-1289
18. Hassan A A, Hassouna M M, Taketo T, Gagnon C, Elhilali MM. The effect of diabetes on sexual behavior and reproductive tract function in male rats[J]. J Urol, 1993, 149(1): 148-154
19. Balasubramanian K, Sivashanmugam P, Thameemdheen S, Govindarajulu P. Effect of diabetes mellitus on epididymal enzymes of adult rats[J]. Indian J Exp Biol, 1991,29(10):907-909
20. Cameron D F, Rountree J, Schultz R E, Repetta D, Murray FT. Sustained hyperglycemia results in testicular dysfunction and reduced fertility potential in BBWOR diabetic rats[J]. Am J Physiol, 1990, 259 (6 Pt 1): E881-E889
21. Seethalakshmi L, Menon M, Diamond D. The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat[J]. J Urol, 1987, 138(1): 190-194
22. Chang A S, Dale A N, Moley K H. Maternal diabetes adversely affects preovulatory oocyte maturation, development, and granulosa cell apoptosis[J]. Endocrinology, 2005,146(5): 2445-2453
23. Colton S A, Humpherson P G, Leese H J, Downs SM. Physiological changes in oocyte-cumulus cell complexes from diabetic mice that potentially influence meiotic regulation[J]. Biol Reprod, 2003, 69(3): 761-770
24. Colton S A, Pieper G M, Downs S M. Altered meiotic regulation in oocytes from diabetic mice[J]. Biol Reprod, 2002, 67(1): 220-231
25. Vesela J, Cikos S, Hlinka D, Rehak P, Baran V, Koppel J. Effects of impaired insulin secretion on the fertilization of mouse oocytes[J]. Hum Reprod, 1995,10(12): 3233-3236
26. Wi J K, Kim J K, Youn J H. Reduced glucose clearance as the major determinant of postabsorptive hyperglycemia in diabetic rats[J]. Am J Physiol, 1998,274 (2 Pt 1): E257-E264
27. Tay Y C, Wang Y, Kairaitis L, Rangan GK, Zhang C, Harris DC. Can murine diabetic nephropathy be separated from superimposed acute renal failure?[J]. Kidney Int, 2005, 68(1): 391-398
28. Van Dam P S, Van Asbeck B S, Bravenboer B, Van Oirschot JF, Marx JJ, Gispen WH. Nerve conduction and antioxidant levels in experimentally diabetic rats: effects of streptozotocin dose and diabetes duration[J]. Metabolism, 1999, 48(4): 442-447
29. Jian K, Fok E, Cam M C, Sambandam N, Yao J, Rodrigues B. Susceptibility of spontaneously hypertensive rats to the diabetogenic effects of streptozotocin[J]. J Physiol Pharmacol, 1996, 74(11): 1215-1221
30. Jin T, Nordberg G, Sehlin J, Vesterberg O. Protection against cadmium-metallothionein nephrotoxicity in streptozotocin-induced diabetic rats: role of increased metallothionein synthesis induced by streptozotocin[J]. Toxicology, 1996, 106(1-3): 55-63
31. Kaufman C R, Catanese V M. Pre- and post-translational regulation of renal insulin-like growth factor binding protein-1 in insulin-deficient diabetes[J]. J Investig Med, 1995,43(2): 178-186
32. Miura H, Iguchi A, Uemura K, Yatomi A, Tamagawa T, Sakamoto N. CNS stimulation does not affect hepatic venous glucose concentration in severely diabetic rats[J]. Am J Physiol, 1991, 260(3 Pt 1): E440-E446
33. Tremblay R R, Trottier L, Abele V, Nadeau A, Gagnon P. Effect of streptozotocin-induced diabetes on insulin binding parameters in adult rat testis[J]. Andrologia, 1985, 17(6): 587-591
34. Rehak P, Mihalik J, Vesela J, Cikos S, Baran V, Koppel J. Effects of impaired maternal insulin secretion on preimplantation embryo development in ICR mice[J]. Physiol Res, 1996, 45(6): 453-458
35. Beebe L F, Kaye P L. Maternal diabetes and retarded preimplantation development of mice[J]. Diabetes, 1991, 40(4): 457-461
1. Ravelli A C, van der Meulen J H, Michels R P, Osmond C, Barker DJ, Hales CN, Bleker OP. Glucose tolerance in adults after prenatal exposure to famine[J]. Lancet, 1998, 351(9097): 173-177
2. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
3. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J]. Diabet Med, 1998, 15(8): 688-694
4. Ito M, Kondo Y, Nakatani A, Hayashi K, Naruse A. Characterization of low dose streptozotocin-induced progressive diabetes in mice[J]. Environ Toxicol Phar, 2001, 9(3): 173-184
5. Pinter E, Reece E A, Leranth C Z, Sanyal M K, Hobbins J C, Mahoney MJ , Naftolin F. Yolk sac failure in embryopathy due to hyperglycemia: ultrastructural analysis of yolk sac differentiation associated with embryopathy in rat conceptuses under hyperglycemic conditions[J]. Teratology, 1986, 33(1): 73-84
6. Hamman R F. Genetic and environment determinants of non-insulin dependent diabetes mellitus[J]. Diabetes Metab Rev, 1992, 8(4):287-338
7. Martin A O, Simpson J L, Ober C, Freinkel N. Frequency of diabetes mellitus in mothers of probands with gestational diabetes, possible maternal influence on the predisposition to gestational diabetes[J]. Am J Obstet Gynecol, 1985, 151(4): 471-475
8. Femandez-Twinn D S, Ozanne S E, Ekizoglou S, Doherty C, James L, Gusterson B, Hales C N. The maternal endocrine environment in the low-protein model of intra-uterine growth restriction [J]. Br J Nutr, 2003, 90(4): 815-822
9. Barker D J, Hales C N, Fall C H, Osmond C, Phipps K, Clark P M. Type 2 (non-insulin-dependent)diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth[J]. Diabetologia, 1993, 36(1): 62-67
10. Femandez-Twinn D S, Wayman A, Ekizoglou S, Martin M S, Hales C N, Ozanne S E. Maternal protein restriction leads to hyperinsulinemia and reduced insulin-signaling protein expression in 2i-mo-old female rat offspring[J]. Am J Physiol Regul Integr Comp Physiol, 2005, 288(2): R368-R373
11. Hales C N, Barker D J. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis[J]. Diabetologia, 1992, 35(7): 595-601
12. Plagemann A, Harder T, Lindner R, Melchior K, Rake A, Rittel F, Rohde W, Dorner G. Alterations of hypothalamic catecholamines in the newborn offspring of gestational diabetic mother rats[J]. Brain Res Dev Brain Res,1998, 109(2): 201-209
13. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J]. Diabet Med, 1998, 15(8): 688-694
14. Ozanne S E, Fernandez-Twinn D, Hales C N. Fetal growth and adult diseases[J]. Semin Perinatol, 2004, 28(1): 81-87
15. Hales C N, Barker D J. The thrifty phenotype hypothesis[J]. Br Med Bull, 2001, 60: 5-20
16. Plagemann A, Harder T, Franke K, et al. Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers[J]. Diabetes Care, 2002,25: 16-22
17. Reusens B, Remacle C. Programming of the endocrine pancreas by the early nutritional environment[J]. Int J Biochem Cell B, 2006, 38(5-6): 913-922
18. Aerts L, Van Assche F A. Intra-uterine transmission of disease[J]. Placenta, 2003, 24(10): 905-911
19 Aerts L, Van Assche F A. Animal evidence for the transgenerational development of diabetes meilitus[J]. Int J Biochem Cell B, 2006, 38(5-6): 894-903
20. Fernandez-Twinn D S, Ozanne S E. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome[J]. Physiol Behav, 2006, 88(3): 234-43
21. Aerts L, Vercruysse L, Van Assche F A. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats[J]. Diabetes Res Clin Pract, 1997, 38(1): 9-19
22. Reusens-Billen B, Remacle C, Daniline J, Hoet J J. Cell proliferation in pancreatic islets of rat fetuses and neonates from normal and diabetic mothers. An in vitro and in vivo study[J]. Horm Metab Res, 1984, 16(11): 565-71
23. Nold J L, Georgieff M K. Infants of diabetic mothers[J]. Pediatr Clin North Am, 2004, 51(3): 619-637
24. Nelson C A, Wewerka S, Thomas K M, Tribby-Walbridge S, deRegnier R, Georgieff M. Neurocognitive sequelae of infants of diabetic mothers[J]. Behav Neurosci, 2000, 114(5): 950-956
25. Lea R G, Andrade L P, Rae M T, Hannah L T, Kyle C E, Murray J F, Rhind S M, Miller D W. Effects of maternal undemutrition during early pregnancy on apoptosis regulators in the ovine fetal ovary[J]. Reproduction, 2006, 131(1): 113-124
26. Sun F, Kawasaki E, Akazawa S, Hishikawa Y, Sugahara K, Kamihira S, Koji T, Eguchi K. Apoptosis and its pathway in early post-implantation embryos of diabetic rats[J]. Diabetes Res Clin Pr, 2005, 67(2): 110-118
27. Phelan S A, Ito M, Loeken M R. Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis[J]. Diabetes, 1997, 46(7): 1189-1197
1. Lucas A. Programming by early nutrition: an experimental approach[J]. J Nutr, 1998, 128 (2 Suppl):401S-406S
2. Kwong W Y, Arthur E, Roberts P, Willis A C, Fleming T P. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension[J]. Development, 2000, 127(19): 4195-4202
3. Booth P J, Holm P, Callesen H. The effect of oxygen tension on porcine embryonic development is dependent on embryo type[J]. Theriogenology, 2005, 63(7):2040-2052
4. Tsai H D, Chang C C, Hsieh Y Y. Recombinant human leukemia inhibitory factor enhances the development of preimplantation mouse embryo in vitro[J]. J Assist Reprod Genet,2000,17(6):352-355
5. Gardner H G, Kaye P L. Insulin increase cell numbers and morphological development in mouse pre-implantation embryos in vitro[J]. Reprod Fertil Dev, 1991, 3(1): 79-91
6. Harvey, M B, Kaye, P L. Insulin stimulates protein synthesis in compacted mouse embryos[J].Endocrinology, 1988,122(3): 1182-1184
7. Harvey M, Kaye P L. Insulin increases the cell number of the immer cell mass and stimulates morphological development of mouse blastocysts in vitro[J]. Develop, 1990,110(3): 963-967
8. Kaye P L, Pemble L, Hobbs J G. Protein metabolism in preimplantation mouse embryos[J]. Prog Clin Biol Res, 1986,217B: 103-106
9. Dunglison G F, Kaye P L. Insulin Regulates Protein Metabolism in Mouse Blastocysts[J]. Mol Reprod Dev, 1993, 36(1): 42-48
10. Martin-Gronert M S, Ozanne S E. Programming of appetite and type 2 diabetes[J]. Early Hum Dev, 2005, 81(12): 981-988
11. Nagy A,Gertsenstein M,Vintersten K, Behringer R 2002. Manipulating the Mouse Embryo:A Laboratory Manual(Third edition ).Cold Spring Harbor Laboratory Press.
12. Bonner-Weir S. Perspective: postnatal pancreatic β cell growth endocrinology [J]. Endocrinology, 2000, 141(6): 1926-1929
13. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
14. Feil R. Environmental and nutritional effects on the epigenetic regulation of genes[J]. Mutat Res, 2006,600(5-6): 46-57
15.Barker D J,Hales C N,Fall C H,Osmond C,Phipps K,Clark P M.Type 2(non-insulin-dependent)diabetes mellitus,hypertension and hyperlipidaemia(syndrome X):relation to reduced fetal growth[J].Diabetologia,1993,36(1):62-67
16.Fernandez-Twinn D S,Wayman A,Ekizoglou S,Martin M S,Hales C N,Ozanne S E.Maternal protein restriction leads to hyperinsulinemia and reduced insulin-signaling protein expression in 21-mo-old female rat offspring[J].Am J Physiol Regul Integr Comp Physiol,2005,288(2):R368-R373
17.Hales C N,Barker D J.Type 2(non-insulin-dependent) diabetes mellitus:the thrifty phenotype hypothesis[J].Diabetologia,1992,35(7):595-601
18.Plagemann A,Harder T,Lindner R,Melchior K,Rake A,Rittel F,Rohde W,Dorner.Alterations of hypothalamic catecholamines in the newborn offspring of gestational diabetic mother rats[J].Brain Res Dev Brain Res,1998,109(2):201-209
19.Martyn C N,Hales C N,Barker D J,Jespersen S.Fetal growth and hyperinsulinaemia in adult life[J].Diabet Med,1998,15(8):688-694
20.Ozanne S E,Fernandez-Twinn D,Hales C N.Fetal growth and adult diseases[J].Semin Perinatol,2004,28(1):81-87
21.Hales C N,Barker D J.The thrifty phenotype hypothesis[J].Br Med Bull,2001,60:5-20
22.Plagemann A,Harder T,Franke K,Kohlhoff R.Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers[J].Diabetes Care,2002,25(1):16-22
23.Reusens B,Remacle C.Programming of the endocrine pancreas by the early nutritional environment[J].Int J Biochem Cell B,2006,38(5-6):913-922
24.Fernandez-Twinn D S,Ozarme S E,Ekizoglou S,Doherty C,James L,Gusterson B,Hales C N.The maternal endocrine environment in the low-protein model of intra-uterine growth restriction[J].Br J Nutr,2003,90(4):815-822
25.白照岱,刘凯,邴鲁军.胰岛素对小鼠早期胚胎体外发育的影响[J].生殖医学杂志,2004,13(5):286-290
26.Aerts L,Van Assche F A.Intra-uterine transmission of disease[J].Placenta,2003,24(10):905-911
27.Martin-Gronert M S,Ozanne S E.Maternal nutrition during pregnancy and health of the offspring[J].Biocheml Soc T,2006,34(5):779-782
28.Taylor P D,Khan I Y,Lakasing L,Dekou V,O'Brien-Coker I,Mallet A I,Hanson M A,Poston L.Uterine artery function in pregnant rats fed a diet supplemented with animal lard[J].Exp Physiol,2003,88(3):389-398
29.Aerts L,Van Assche F A.Animal evidence for the transgenerational development of diabetes mellitus[J]. Int J Biochem Cell B, 2006, 38(5-6): 894-903
30. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic[J]. Diabetes, 2005, 54(7): 1899-1906
1. Reusens-Billen B, Remacle C, Daniline J, Hoet J J. Cell proliferation in pancreatic islets of rat fetuses and neonates from normal and diabetic mothers. An in vitro and in vivo study [J]. Horm Metab Res, 1984, 16(11): 565-571
2. Kervran A, Guillaume M, Jost A. The endocrine pancreas of the fetus from diabetic pregnant rat[J]. Diabetologia, 1978, 15(5): 387-393
3. Aerts L, Vercruysse L, Van Assche F A. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats[J]. Diabetes Res Clin Pract, 1997, 38(1): 9-19
4. Tay Y C, Wang Y, Kairaitis L, Rangan G K, Zhang C, Harris D C. Can murine diabetic nephropathy be separated from superimposed acute renal failure?[J] Kidney Int, 2005, 68(1): 391-398
5. Wi J K, Kim J K, Youn J H. Reduced glucose clearance as the major determinant of postabsorptive hyperglycemia in diabetic rats[J]. Am J Physiol, 1998, 274(2 Pt 1): E257-E264
6. Jian K, Fok E, Cam M C, Yao J, Rodrigues B. Susceptibility of spontaneously hypertensive rats to the diabetogenic effects of streptozotocin[J]. Can J Physiol Pharmacol, 1996,74(11):1215-1221
7. Soudamani S, Yuvaraj S, Malini T, Balasubramanian K. Experimental diabetes has adverse effects onthe differentiation of ventral prostate during sexual maturation of rats[J]. Anat Rec A Discov Mol Cell Evol Biol, 2005, 287(2): 1281-1289
8. Cameron D F, Rountree J, Schultz R E, Repetta D, Murray F T. Sustained hyperglycemia results in testicular dysfunction and reduced fertility potential in BBWOR diabetic rats[J]. Am J Physiol, 1990, 259(6 Pt 1):E881-E889
9. Beebe L F, Kaye P L. Maternal diabetes and retarded preimplantation development of mice[J]. Diabetes, 2001, 40(4): 457-461
10. Diamond M P, Moley K H, Pellicer A, Vaughn W K, DeCherney A H. Effects of streptozotocin and alloxan-induced diabetes mellitus on mouse follicular and early embryo development[J]. J Reprod Fertil, 1989, 86(1):1-10.
11. De Hertogh R, Vanderheyden I, Pampfer S, Robin D, Dufrasne E, Delcourt J. Stimulatory and inhibitory effects of glucose and insulin on rat blastocyst development in vitro[J]. Diabetes, 1991, 40(5): 641-647
12. Mihalik J, Rehak P, Koppel J. The influence of insulin on the in vitro development of mouse and bovine embryos[J]. Physiol Res, 2000, 49(3): 347-354
13. Lea R G, Andrade L P, Rae M T, Hannah L T, Kyle C E, Murray J F, Rhind S M, Miller D W. Effects of maternal undemutrition during early pregnancy on apoptosis regulators in the ovine fetal ovary[J]. Reproduction, 2006, 131(11): 113-124
14. Rehak P, Mihalik J, Vesela J, Cikos S, Baran V, Koppel J. Effects of impaired maternal insulin secretion on preimplantation embryo development in ICR mice[J]. Physiol Res, 1996, 45(6): 453-458
15. Sadler T W. Effects of maternal diabetes on early embryogenesis: I. The teratogenic potential of diabetic serum[J]. Teratology, 1980, 21(3): 339-347
16. Sadler T W. Effects of maternal diabetes on early embryogenesis: II. Hyperglycemia-induced exencephaly[J]. Teratology, 1980, 21(3): 349-356
17．李云龙,刘春巧．动物发育生物学[M]．山东,2003：549-561
18. Bartolomei M S, Zemel S, Tilghman S M. Parental imprinting of the mouse H19 gene[J]. Nature, 1991,351(6322): 153-155
19. DeChiara T M, Robertson E J, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene[J]. Cell, 1991,64(4):849-859
20. Dunglison G F, Kaye P L. Insulin Regulates Protein Metabolism in Mouse Blastocysts[J]. Mol ReprodDev, 1993, 36(1): 42-48
21. Khosla S, Dean W, Brown D, Reik W, Feil R. Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes[J]. Biol Reprod, 2001,64(3): 918-926
22.Thorvaldsen J L, Duran K, Bartolomei M S. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2[J]. Genes Dev, 1998,12(23): 3693-3702
23. Hsieh C L. Dynamics of DNA methylation pattern[J]. Curr Opin Genet Dev, 2000,10(2): 224-228
24. Feil R, Walter J, Allen N D, Reik W. Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes[J]. Develop, 1994,120(10): 2933-2943
25. Ungaro P, Casola S, Vernucci M, Pedone P V, Bruni C B, Riccio A. Relaxation of insulin-like growth factor-2 imprinting in rat cultured cells[J].Mol Cell Endocrinol, 1997,135(2):153-63
26.Thorvaldsen J L, Duran K L, Bartolomei M S. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2[J]. Genes Dev, 1998, 12(23):3693-3702
27. Wu Q, Ohsako S, Ishimura R, Suzuki J S, Tohyama C. Exposure of Mouse Preimplantation Embryos to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Methylation Status of Imprinted Genes H19 and Igf2[J]. Biol Reprod, 2004, 70(6): 1790-1797
28. Livak K J, Schmittgen T D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T) )method[J]. Methods, 2001, 25 (4): 402-408
29. Vambergue A, Fajardy I, Dufour P, Valat A S, Vandersippe M, Fontaine P, Danze P M, Rousseaux J. No loss of genomic imprinting of IGF-II and H19 in placentas of diabetic pregnancies with fetal macrosomia[J]. Growth Horm IGF Res, 2007, 17(2): 130-136
30. Zhu B, Huang X, Chen J, Lu Y, Chen Y, Zhao J. Methylation changes of H19 gene in sperms of X-irradiated mouse and maintenance in offspring[J]. Biochem and Biophy Res Commu, 2006, 340(1): 83-89
31. Junien C, Gallou-Kabani C, Vige A, Gross M S. Nutritional epigenomics of metabolic syndrome[J]. Med Sci (Paris), 2005, 21(4): 44-52
32. Junien C, Gallou-Kabani C, Vige A, Gross M S. Nutritionnal epigenomics: consequences of unbalanced diets on epigenetics processes of programming during lifespan and between generations[J]. Ann Endocrinol (Paris), 2005, 66(2 Pt 3): 2S19-28
33. Waterland R A, Dolinoy D C, Lin J R, Smith C A, Shi X, Tahiliani K G. Maternal methyl supplements increase offspring DNA methylation at Axin Fused[J]. Genesis, 2006, 44(9): 401-406
34. Doherty A S, Mann M R, Tremblay K D, Bartolomei M S, Schultz R M. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo[J]. Biol Reprod, 2000, 62(6): 1526-1535
1. Harvey M B, Kaye P L. Insulin stimulates protein synthesis in compacted mouse embryos[J]. Endocrinology, 1988,122(3): 1182-1184
2. Harvey M B, Kaye P L. Insulin increases the cell number of the immer cell mass and stimulates morphological development of mouse blastocysts in vitro[J]. Develop, 1990, 110(3): 963-967
3. Kaye P L, Pemble L B, Hobbs J G. Protein metabolism in preimplantation mouse embryos[J]. Prog Clin Biol Res, 1986, 217B: 103-106
4. Gardner H G, Kaye P L. Insulin increase cell numbers and morphological development in mouse pre-implantation embryos in vitro[J]. Reprod Fertil Dev, 1991, 3(1): 79-91
5. Dunglison G F, Jane S D, McCaul T F, Chad J E, Fleming T P, Kaye P L. Stimulation of endocytosis in mouse blastocysts by insulin: a quantitative morphological analysis[J]. J Reprod Fertil, 1995, 105(1): 115-123
6. Rosenblum I Y, Mattson B A, Heyner S. Stage-specific insulin binding in mouse preimplantation embryos[J]. Dev Biol, 1986,116(1): 261-263
7. Kaye P L, Bell K L, Beebe L F, Dunglison G F, Gardner H G, Harvey M B. Insulin and the insulin-like growth factors (IGFs) in preimplantation development[J]. Reprod Fertil Dev, 1992, 4(4): 373-386
8. Mattson B A, Rosenblum I Y, Smith R M, Heyner S. Autoradiographic evidence for insulin and insulin-like growth factor binding to early mouse embryo[J]. Diabetes, 1988,37(5):585-589
9. Dunglison G F, Kaye P L. Insulin Regulates Protein Metabolism in Mouse Blastocysts[J]. Mol Reprod Dev, 1993, 36(1): 42-48
10. Bartolomei M S, Zemel S, Tilghman S M. Parental imprinting of the mouse H19 gene[J]. Nature, 1991,351(6322):153-155
11. DeChiara T M, Robertson E J, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene[J]. Cell, 1991,64(4):849-859
12. Khosla S, Dean W, Brown D, Reik W, Feil R. Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes[J]. Biol Reprod, 2001, 64(3): 918-926
13. Hsieh C L. Dynamics of DNA methylation pattem[J]. Curr Opin Genet Dev, 2000, 10(2): 224-228
14. Thorvaldsen J, Duran K L, Bartolomei M S. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2[J]. Genes Dev, 1998,12(23): 3693-3702
15. Feil R, Walter J, Allen N D. Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes[J]. Develop, 1994, 120(10): 2933-2943
16. Wu Q, Ohsako S, Ishimura R, Suzuki J S, Tohyama C. Exposure of Mouse Preimplantation Embryos to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Alters the Methylation Status of Imprinted Genes H19 and Igf2[J]. Biol Reprod, 2004, 70(6): 1790-1797
17. Zhu B, Huang X H, Chen J D, Lu Y C, Chen Y, Zhao J Y. Methylation changes of H19 gene in sperms of X-irradiated mouse and maintenance in offspring[J]. Biochem and Biophy Res Commu, 2006, 340(1): 83-89
18. Nagy A, Gertsenstein M, Vintersten K, Behringer R. Manipulating the Mouse Embryo:a laboratory manual 3rd ed .Cold Spring Harbor(NY):Cold Spring Harbor Laboratory Press. 2002.
19. Herrler A, Krusche C A, Beier H M. Insulin and insulin-like growth factor-I promote rabbit blastocyst development and prevent apoptosis[J]. Biol Reprod, 1998, 59(6): 1302-1310
20. Heyner S. Growth factors in preimplantation development: role of insulin and insulin-like growth factors[J]. Early Pregnancy. 1997, 3(3):153-163
21. Hiden U, Maier A, Bilban M, Ghaffari-Tabrizi N, Wadsack C, Lang I, Dohr G. Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy [J]. Diabetologia, 2006,49(1): 123-131
22. Kobayashi H, Suda C, Abe T, Kohara Y, Ikemura T, Sasaki H. Bisulfite sequencing and dinucleotide content analysis of 15 imprinted mouse differentially methylated regions (DMRs): paternally methylated DMRs contain less CpGs than maternally methylated DMRs[J]. Cytogenet Genome Res, 2006,113(1-4): 130-137
23. Serman A, Vlahovic M, Serman L, Bulic-Jakus F. DNA Methylation as a regulatory mechanism for gene expression in mammals[J]. Coll Antropol, 2006, 30(3): 665-671
24. Gebert C, Wrenzycki C, Herrmann D, Groger D, Reinhardt R, Hajkova P, Lucas-Hahn A, Carnwath J, Lehrach H, Niemann H. The bovine IGF2 gene is differentially methylated in oocyte and sperm DNA[J]. Genomics, 2006, 88(2): 222-229
25. Dean W, Bowden L, Aitchison A, Klose J, Moore T, Meneses J J, Reik W, Feil R. Altered imprinted gene methylation and expression in completely ES cell derived mouse fetuses: association with aberrant phenotypes[J]. Develop, 1998, 125(12): 2273-2282
26. Ungaro P, Casola S, Vernucci M, Pedone P V, Bruni C B, Riccio A. Relaxation of insulin-like growth factor-2 imprinting in rat cultured cells[J]. Mol Cell Endocrinol, 1997, 135(2): 153-163
27. Sasaki H, Ferguson-Smith A C, Shum A S, Barton S C, Surani M A. Temporal and spatial regulation of H19 imprinting in normal and uniparental mouse embryos[J]. Develop, 1995, 121(12): 4195-4202
28. Sinclair K D, Young L E, Wilmut I, McEvoy T G. In utero overgrowth in ruminants following embryo culture:Lessons from mice and a warning to men[J]. Hum Reprod, 2000, Supplement: 68-86
29. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic[J]. Diabetes, 2005, 54(7): 1899-1906
30. Waterland R A, Garza C. Potential mechanisms of metabolic imprinting that lead to chronic disease[J]. Am J Clin Nutr, 1999, 69(2): 179-197
31. Cherif H, Reusens B, Dahri S Remacle C, Hoet J J. Stimulatory effects of taurine on insulin secretion by fetal rat islets cultured in vitro[J]. J Endocrinol, 1996,151(3): 501-506
32. Warnecke P M, Mann J R, Frommer M, Clark S J. Bisulfite Sequencing in Preimplantation Embryos: DNA Methylation Profile of the Upstream Region of the Mouse Imprinted H19 Gene[J]. Genomics, 1998,51(2): 182-190
33. Liu J, Nealon J G, Weinstein L S. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB [J]. Hum Mol Genet, 2005, 14(1): 95-102
34. Chen T, Ueda Y, Dodge J E, Wang Z, Li E. Establishment and Maintenance of Genomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b[J]. Mol Cell Biol, 2003, 23(16): 5594-5605
35. Okano M, Bell D W, Haber D A, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development[J]. Cell, 1999, 99(3): 247-257
36. Hata K, Okano M, Lei H, Li E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice[J]. Develop, 2002, 129(8): 1983-1993
1. Ravelli A C, van der Meulen J H, Michels R P, Osmond C, Barker D J, Hales C N, Bleker O P. Glucose tolerance in adults after prenatal exposure to famine[J]. Lancet, 1998(9097), 351: 173-177
2. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev. 1990, 6(3): 147-167
3. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J]. Diabet Med, 1998, 15(8): 688-694
4. Ito M, Kondo Y, Nakatani A, Hayashi K, Naruse A. Characterization of low dose streptozotocin-induced progressive diabetes in mice[J]. Environ Toxicol and Phar, 2001, 9(3): 173-184
5. Pinter E, Reece E A, Leranth C Z, Sanyal M K, Hobbins J C, Mahoney M J, Naftolin F. Yolk sac failure in embryopathy due to hyperglycemia: ultrastructural analysis of yolk sac differentiation associated with embryopathy in rat conceptuses under hyperglycemic conditions[J]. Teratology, 1986, 33(1): 73-84
6. Martyn C N, Hales C N, Barker D J, Jespersen S. Fetal growth and hyperinsulinaemia in adult life[J].Diabet Med, 1998, 15(8): 688-694
7. Ozanne S E, Fernandez-Twinn D, Hales C N. Fetal growth and adult diseases[J]. Semin Perinatol, 2004, 8(1): 81-87
8. Phelan S A., Ito M., Loeken M R. Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis[J]. Diabetes, 1997, 46(7): 1189-1197
9. Sun F, Kawasakia E, Akazawac S, Hishikawa Y, Sugahara K, Kamihira S, Koji T, Eguchi K. Apoptosis and its pathway in early post-implantation embryos of diabetic rats Diabetes[J]. Res and Clin Pr, 2005, 67(2): 110-118
10. Ilany J, Bilan P J, Kapur S, Caldwell J S, Parti M E, Marette A, Kahn C R. Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level[J]. Proc Nat Acad Sci, 2006, 103(12): 4481-4486
11. Reynet C, Kahn C R. Rad: a member of the Ras family overexpressed in muscle of type II diabetic humans[J]. Science, 1993, 262(5138): 1441-1444
12. Nold J L, Georgieff M K. Infants of diabetic mothers[J]. Pediatr Clin North Am, 2004, 51(3): 619-637
13. Nelson C A, Wewerka S, Thomas K M, Tribby-Walbridge S, deRegnier R, Georgieff M. Neurocognitive sequelae of infants of diabetic mothers[J]. Behav Neurosci, 2000,114(5): 950-956
14. Hata K, Okano M, Lei H, Li E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice[J]. Develop, 2002, 129(8): 1983-1993
15. Okano M, Bell D W, Haber D A, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development[J]. Cell, 1999, 99(3): 247-257
16. Chen T P, Ueda Y, Dodge J E, Wang Z, Li E. Establishment and Maintenance of Genomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b[J]. Mol Cell Biol, 2003, 23(16): 5594-5605
17. Wentzel P, Wentzel C R, Gareskog M B, Wentzel P, Wentzel C R, Gareskog M B, Eriksson U J. Induction of embryonic dysmorphogenesis by high glucose concentration, disturbed inositol metabolism, and inhibited protein kinase C activity[J]. Teratology, 2001,63(5): 193-201
18. Reece EA, Ji I, Wu YK, Zhao Z. Characterization of differential gene expression profiles in diabetic embryopathy using DNA microarray analysis[J]. Am J Obstet Gynecol, 2006,195(4): 1075-1080
1. Beebe L F, Kaye P L. Maternal diabetes and retarded preimplantation development of mice[J]. Diabetes, 2001,40(4): 457-461
2. Diamond M P, Moley K H, Pellicer A, Vaughn W K, DeCherney A H. Effects of streptozotocin and alloxan-induced diabetes mellitus on mouse follicular and early embryo development[J]. J Reprod Fertil 1989, 86(1):1-10
3. De Hertogh R, Vanderheyden I, Pampfer S, Robin D, Dufrasne E, Delcourt J. Stimulatory and inhibitory effects of glucose and insulin on rat blastocyst development in vitro[J]. Diabetes, 1991, 40(5): 641-647
4. Mihalik J, Rehak P, Koppel J. The influence of insulin on the in vitro development of mouse and bovine embryos[J]. Physiol Res, 2000, 49(3): 347-354
5. Lea R G, Andrade L P, Rae M T, Hannah L T, Kyle C E, Murray J F, Rhind S M, Miller D W. Effects of maternal undernutrition during early pregnancy on apoptosis regulators in the ovine fetal ovary[J]. Reproduction, 2006,131(1): 113-124
6. Rehak P, Mihalik J, Vesela J, Cikos S, Baran V, Koppel J. Effects of impaired maternal insulin secretion on preimplantation embryo development in ICR mice[J]. Physiol Res, 1996, 45(6): 453-458
7. Aerts L, Holemans K, Van Assche F A. Maternal diabetes during pregnancy: consequences for the offspring[J]. Diabetes Metab Rev, 1990, 6(3): 147-167
8 Reusens-Billen B, Remacle C, Daniline J, Hoet J J. Cell proliferation in pancreatic islets of rat fetuses and neonates from normal and diabetic mothers. An in vitro and in vivo study[J]. Horm Metab Res, 1984, 16(11): 565-571
9. Aerts L, Vercruysse L, Van Assche F A. The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats[J]. Diabetes Res Clin Pract, 1997, 38(1): 9-19
10. Chang A S, Dale A N, Moley K H. Maternal diabetes adversely affects preovulatory oocyte maturation, development, and granulosa cell apoptosis[J]. Endocrinology, 2005,146(5): 2445-2453
11. Colton S A, Humpherson P G, Leese H J, Downs SM. Physiological changes in oocyte-cumulus cell complexes from diabetic mice that potentially influence meiotic regulation[J]. Biol Reprod, 2003, 69(3): 761-770
12. Colton S A, Pieper G M, Downs S M. Altered meiotic regulation in oocytes from diabetic mice[J]. Biol Reprod, 2002,67(1): 220-231
13.Vesela J,Cikos S,Hlinka D,Rehak P,Baran V,Koppel J.Effects of impaired insulin secretion on the fertilization of mouse oocytes[J].Hum Reprod,1995,10(12):3233-3236
14.Wi J K,Kim J K,Youn J H.Reduced glucose clearance as the major determinant of postabsorptive hyperglycemia in diabetic rats[J].Am J Physiol,1998,274(2 Pt 1):E257-E264
15.Scarano W R,Messias A G,Oliva S U,Klinefelter GR,Kempinas WG.Sexual behaviour,sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats[J].Int J Androl,2006,29(4):482-488
16.Soudamani S,Malini T,Balasubramanian K.Effects of streptozotocin-diabetes and insulin replacement on the epididymis of prepubertal rats:histological and histomorphometric studies[J].Endocr Res,2005,31(2):81-98
17 Soudamani S,Yuvaraj S,Malini T,Balasubramanian K.Experimental diabetes has adverse effects on the differentiation of ventral prostate during sexual maturation of rats[J].Anat Rec A Discov Mol Cell Evol Biol,2005,287(2):1281-1289
18.Hassan A A,Hassouna M M,Taketo T,Gagnon C,Elhilali M M.The effect of diabetes on sexual behavior and reproductive tract function in male rats[J].J Urol,1993,149(1):148-154
19.Balasubramanian K,Sivashanmugam P,Thameemdheen S,Govindarajulu P.Effect of diabetes mellitus on epididymal enzymes of adult rats[J].Indian J Exp Biol,1991,29(10):907-909
20.Cameron D F,Rountree J,Schultz R E,Repetta D,Murray F T.Sustained hyperglycemia results in testicular dysfunction and reduced fertility potential in BBWOR diabetic rats[J].Am J Physiol,1990,259(6 Pt 1):E881-E889
21.Seethalakshmi L,Menon M,Diamond D.The effect of streptozotocin-induced diabetes on the neuroendocrine-male reproductive tract axis of the adult rat[J].J Urol,1987(1),138:190-194
22.孙丽霞,周丛乐,王红梅,等.母亲孕期糖尿病对子代脑发育影响的研究[J].中华围产医学杂志,2004,7(6):346-348
23.陈晓霞,周丛乐,王红梅,等.糖尿病母亲婴儿脑发育状况的研究[J].中华围产医学杂志,2005,8(5):300-303
24.Aerts L,Van Assche F A.Animal evidence for the transgenerational development of diabetes mellitus[J].Int J Biochem Cell B,2006,38(5-6):894-903
25.Harvey M B,Kaye P L.Insulin stimulates protein synthesis in compacted mouse embryos[J].Endocrinology,1988,122(3):1182-1184
26.Harvey M,Kaye P L.Insulin increases the cell number of the immer cell mass and stimulates morphological development of mouse blastocysts in vitro[J].Develop,1990,110(3):963-967
27.Kaye P L,Pemble L,Hobbs J G.Protein metabolism in preirnplantation mouse embryos[J].Prog Clin Biol Res, 1986, 217B: 103-106
28. Dunglison G F, Kaye P L. Insulin Regulates Protein Metabolism in Mouse Blastocysts[J]. Mol Reprod Dev, 1993, 36(1): 42-48
29. Martin-Gronert M S, Ozanne S E. Maternal nutrition during pregnancy and health of the offspring[J]. Biochem Soe T, 2006, 34(5): 779-782
30. Gerber R T, Holemans K, O'Brien-Coker I, Mallet A I, van Bree R, Van Assche F A, Poston L. Cholesterol-independent endothelial dysfunction in virgin and pregnant rats fed a diet high in saturated fat [J].J Physiol, 1999, 517(Pt 2): 607-616
31. Taylor P D, Khan I Y, Lakasing L, Dekou V, O'Brien-Coker I, Mallet A I, Hanson M A, Poston L. Uterine artery function in pregnant rats fed a diet supplemented with animal lard [J].Exp Physiol, 2003, 88(3): 389-398
32. Sasaki H, Ferguson-Smith A C, Shum A S, Barton S C, Surani M A. Temporal and spatial regulation of H19 imprinting in normal and uniparental mouse embryos[J]. Develop, 1995,121(12): 4195-4202
33. Doherty A S, Mann M R, Tremblay K D, Bartolomei M S, Schultz R M. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo[J]. Biol Reprod, 2000, 62(6): 1526-1535
34. Waterland R A, Lin J R, Smith C A, Jirtle R L. Post-weaning diet affects genomic imprinting at the insulin-like growth factor2 (Igf2) locus[J]. Hum Mol Genet, 2006,15(5): 705-716
35. Weber M, Hagege H, Murrell A, Brunei C, Reik W, Cathala G, Forne T. Genomic imprinting controls matrix attachment regions in the Igf2 gene[J]. Mol Cell Biol, 2003, 23(24): 8953-8959
36. Kobayashi H, Suda C, Abe T, Kohara Y, Ikemura T, Sasaki H. Bisulfite sequencing and dinucleotide content analysis of 15 imprinted mouse differentially methylated regions (DMRs): paternally methylated DMRs contain less CpGs than maternally methylated DMRs[J]. Cytogenet Genome Res, 2006, 113(1-4): 130-137
37. Reik W, Dean W. DNA methylation and mammalian epigenetics[J]. Electrophoresis, 2001, 22(14): 2838-4283
38. Gebert C, Wrenzycki C, Herrmann D, Groger D, Reinhardt R, Hajkova P, Lucas-Hahn A, Carnwath J, Lehrach H, Niemann H. The bovine IGF2 gene is differentially methylated in oocyte and sperm DNA[J]. Genomics, 2006, 88(2): 222-229
39. Serman A, Vlahovic M, Serman L, Bulic-Jakus F. DNA Methylation as a regulatory mechanism for gene expression in mammals[J]. Coll Antropol, 2006,30(3):665-671
40. Warnecke P M, Mann J R, Frommer M, Clark S J. Bisulfite Sequencing in Preimplantation Embryos: DNA Methylation Profile of the Upstream Region of the Mouse Imprinted H19 Gene[J]. Genomics, 1998,51(2): 182-190
41. Chen T, Ueda Y, Dodge J E, Wang Z, Li E. Establishment and Maintenance of Genomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b[J]. Mol Cell Biol, 2003, 23(16): 5594-5605
42. Okano M, Bell D W, Haber D A, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development[J]. Cell, 1999, 99(3): 247-257
43. Hata K, Okano M, Lei H, Li E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice[J]. Develop, 2002, 129(8): 1983-1993
44. Ilany J, Bilan PJ, Kapur S, Caldwell J S, Patti M E, Marette A, Kahn C R. Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level[J]. Proc Nat Acad Sci, 2006, 103(12): 4481-4486
45. Reynet C, Kahn C R. Rad: a member of the Ras family overexpressed in muscle of type II diabetic humans[J]. Science, 1993, 262(5138): 1441-1444