Dietary interventions to modulate heart health in offspring born to diabetic mothers and the subsequent generation.

妊娠糖尿病和肥胖症使胎儿在发育的关键窗口期营养过剩。有证据表明，胎儿营养过剩会增加出生时和以后生活中患心脏病的风险。更重要的是，程序化的风险可以传递给下一代。我们实验室的目标是开发有效的干预措施，改善这一容易识别的人群的心脏健康，随着时间的推移减轻心脏病的负担。为了了解母体饮食在发育性程序性心脏病中的作用，我们开发了一种大鼠模型，比较了对照组、糖尿病组、高脂饮食组和联合暴露组后代的结局。我们发现，就像人类一样，大鼠的胎儿营养过剩会导致出生时和成年时的心脏功能障碍。我们还证明，心脏的后果是由于线粒体功能障碍，心肌细胞代谢受损，代谢应激后细胞死亡加快。重要的是，我们发现母体高脂肪饮食会夸大线粒体和心脏功能障碍，从而增加糖尿病母亲（ODM）所生后代的死亡率，特别是通过增加胎儿营养过剩和编程心脏转录组更容易受到氧化损伤。虽然我们的工作突出了母亲膳食脂肪摄入的作用，但有关编程的关键问题仍然存在：1。氧化性DNA损伤是否会导致ODM和下一代的程序性心脏病？2.在怀孕的最后三个月限制脂肪摄入会降低风险吗？3.膳食抗氧化剂辅酶Q（CoQ 10）可以预防ODM及其后代的程序性心脏病吗？目标1将使用创新的基因组方法与跨代心脏表型配对，以确定氧化DNA损伤是否有助于胎儿营养过剩后的程序性心脏病。作为ROS的主要生产者，功能障碍的线粒体可以以8-氧代-7，8-二氢-2 '-脱氧鸟苷（8-oxodG）的形式引起氧化性DNA损伤，这是一种易于错误修复和基因组不稳定的诱变性损伤。来自8-oxodG的基因组扰动与代谢疾病、早期衰老和炎症有关;此外，它们可能是可遗传的。我们将通过使用oxiDIP-seq比较全基因组水平和下游基因组扰动来确定8-oxodG是否有助于我们模型中的程序性心脏病。我们还将使用来自F0雌性及其F1和F2后代的囊胚的scRNA-sequencing来描述新获得的突变的时间以及跨代DNA修复机制是否存在复合或稀释。目的2和3将确定饮食干预，包括在怀孕的最后三分之一限制膳食脂肪摄入或在排卵和受精期间补充高风险女性膳食辅酶Q10，是否会降低ODM及其后代患发育性程序性心脏病的风险。研究结果需要了解机制，遗传模式和临床适用的干预措施，如扩大糖尿病筛查和饮食咨询，包括管理产妇高脂血症以及高血糖症或在计划生育期间提供预防性膳食补充剂的影响。

Gestational diabetes and obesity expose the fetus to overnutrition during critical windows of development. Evidence shows that fetal overnutrition increases the risk of heart disease at birth and later in life. What’s more, programmed risk can be passed on to the next generation. The goal of our lab is to develop effective interventions that improve heart health in this readily identifiable population, lessening the burden of heart disease over time. To understand the role of maternal diet in developmentally programmed heart disease, we developed a rat model that compared outcomes of control, diabetes-, high-fat diet-, and combination-exposed offspring. We found that, just like in humans, fetal overnutrition in rats causes cardiac dysfunction at birth and again in adulthood. We also demonstrated that cardiac consequences are due to mitochondrial dysfunction, impaired cardiomyocyte metabolism, and faster cell death following metabolic stress. Importantly, we found that a maternal high-fat diet exaggerates mitochondrial and cardiac dysfunction to increase mortality in offspring born to diabetic mothers (ODM), specifically by increasing fetal overnutrition and programming the cardiac transcriptome to be more susceptible to oxidative damage. While our work highlights the role of maternal dietary fat intake, key questions about programming remain: 1. Does oxidative DNA damage contribute to programmed heart disease in ODM and the next generation? 2. Will limiting fat intake during the last trimester of pregnancy mitigate risks? 3. Can the dietary antioxidant Coenzyme Q (CoQ10) prevent programmed heart disease in ODM and their progeny? Aim 1 will use innovative genomic approaches paired with cardiac phenotyping across generations to establish whether oxidative DNA damage contributes to programmed heart disease following fetal overnutrition. As primary producers of ROS, dysfunctional mitochondria can cause oxidative DNA damage in the form of 8-oxo- 7,8-dihydro-2’-deoxyguanosine (8-oxodG), a mutagenic lesion prone to misrepair and genome instability. Genomic perturbations from 8-oxodG have been linked to metabolic disease, early ageing, and inflammation; moreover, they may be inheritable. We will determine whether 8-oxodG contributes to programmed heart disease in our model by comparing whole genome levels and downstream genomic perturbations using oxiDIP-seq. We will also use scRNA-sequencing of blastocysts from F0 females and their F1 and F2 offspring to delineate the timing of newly acquired mutations and whether there is compounding or dilution from DNA repair mechanisms across generations. Aims 2 and 3 will determine whether dietary interventions including limiting dietary fat intake in the last third of pregnancy or supplementing high-risk females with dietary CoQ10 during ovulation and fertilization will decrease the risk of developmentally programmed heart disease in ODM and their progeny. Findings are needed to understand mechanisms, inheritance patterns, and the effects of clinically applicable interventions such as expanding diabetic screening and dietary counseling to include management of maternal hyperlipidemia as well as hyperglycemia or offering preventative dietary supplementation during family planning.