Intrauterine Programming of Diabetes Induced Cardiac Embryopathy.

Diabetes & obesity international journal Pub Date : 2019-01-01 Epub Date: 2019-05-06
Rolanda Lister, Alyssa Chamberlain, Francine Einstein, Bingruo Wu, DeYou Zheng, Bin Zhou
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Abstract

Background: Maternal hyperglycemia is a well-recognized risk factor for fetal congenital heart disease. However, the underlying cellular and molecular mechanisms are not well characterized. We hypothesize that maternal hyperglycemia leading to congenital heart are linked to abnormal DNA methylation and mRNA expression at cardiac specific loci.

Methods: Hyperglycemia was induced in normal 8-week old CD-1 female mice with a one-time intraperitoneal injection of 150 mg/kg of streptozotocin (STZ) 2 weeks prior to mating. Histological analysis of fetal cardiac morphology was evaluated for malformations on embryonic day (E) 16.5 of control pups and pups exposed to maternal hyperglycemia. We used a massively-parallel sequencing-based methylation sensitive restriction based assay to examine genome-wide cytosine methylation levels at >1.65 million loci in neonatal hearts on post-natal (P) day 0. Functional validation was performed with real time quantitative polymerase chain reaction (RT-qPCR).

Results: Cardiac structural defects occurred in 28% of the pups (n=12/45) of hyperglycemic dams versus 7% (n=4/61) of controls. Notable phenotypes were hypoplastic left or right ventricle, double outlet right ventricle, ventricular septal defect, and left ventricular outflow tract obstruction. A 10-fold increase in DNA methylation of gene promoter regions was seen in many cardiac important genes in the experimental versus control P0 neonates and have corresponding decreases in gene expression in 21/32 genes functionally validated.

Conclusion: Maternal hyperglycemia alters DNA methylation and mRNA expression of some cardiac genes during heart development. Quantitative, genome-wide assessment of cytosine methylation can be used as a discovery platform to gain insight into the mechanisms of hyperglycemia-induced cardiac anomalies.

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糖尿病诱发心脏胚胎病的宫内程序设计。
背景:母体高血糖是胎儿先天性心脏病的一个公认的危险因素。然而,潜在的细胞和分子机制尚未很好地表征。我们假设导致先天性心脏病的母体高血糖与心脏特定位点的异常DNA甲基化和mRNA表达有关。方法:在交配前2周一次性腹腔注射链脲佐菌素(STZ) 150 mg/kg,诱导8周龄正常CD-1雌性小鼠出现高血糖。在胚胎日(E) 16.5时,对对照组和暴露于母体高血糖的幼崽进行胎儿心脏形态的组织学分析。我们使用基于大规模平行测序的甲基化敏感限制性测定来检测出生后第0天新生儿心脏中> 165万个位点的全基因组胞嘧啶甲基化水平。采用实时定量聚合酶链反应(RT-qPCR)进行功能验证。结果:28%的高血糖鼠(n=12/45)发生心脏结构缺陷,而对照组(n=4/61)为7%。显著表型为左、右心室发育不全,右心室双出口,室间隔缺损,左心室流出道梗阻。与对照组相比,在实验P0新生儿中,许多心脏重要基因的基因启动子区域的DNA甲基化增加了10倍,而在功能验证的21/32个基因中,基因表达相应减少。结论:母体高血糖会改变心脏发育过程中一些心脏基因的DNA甲基化和mRNA表达。胞嘧啶甲基化的定量全基因组评估可以作为一个发现平台,以深入了解高血糖诱导的心脏异常的机制。
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