Maternal Fetal Metabolic Disruption in Prenatal Alcohol Exposure

产前酒精暴露导致母体胎儿代谢紊乱

• 批准号: 10301279
• 负责人: Nipun Saini
• 金额: $ 13.77万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301279
• 关键词: Address; Affect; Alcohol consumption; Alcohols; Amino Acids; Animals; Area; Behavior assessment; Behavioral; Biological Assay; Brain; Catabolism; Clinical; Cognitive deficits; Data; Development; Dysmorphology; Embryo; Energy Metabolism; Energy-Generating Resources; Face; Failure; Fasting; Fatty Acids; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Growth; Fetal Growth Retardation; Fetal Liver; Fetal Weight; Fetus; Fingerprint; Functional disorder; Future; Genetic; Gluconeogenesis; Glucose; Glucose tolerance test; Glycogen; Goals; Growth; Growth and Development function; Hepatic; Hormones; Hypoglycemia; Impaired cognition; Impairment; Insulin; Insulin Resistance; Intervention; Knockout Mice; Knowledge; Lead; Leptin; Leptin resistance; Liver; Mediating; Metabolic; Metabolism; Methodology; Methods; Modeling; Modification; Mus; Neurodevelopmental Deficit; Nutrient; Organ; Outcome; Phase; Placental Lactogen; Plasma; Pregnancy; Pregnant Women; Prolactin; Public Health; Research; Risk Factors; Severities; Signal Transduction; Skeletal Muscle; Testing; Tracer; Training; Transgenic Mice; Triglycerides; Urea; Weight; Work; alcohol effect; alcohol exposure; alcohol intervention; alcohol prevention; alcohol testing; at-risk pregnancies; base; behavioral impairment; clinically relevant; cognitive function; disability; fasting glucose; fetal; glucose metabolism; improved; insight; insulin sensitivity; insulin signaling; lead candidate; leptin receptor; liver metabolism; loss of function; metabolic abnormality assessment; metabolic profile; mouse model; neglect; neurobehavioral; novel; nutrition; offspring; oxidation; pregnant; programs; response; skills

Project Summary Despite public health efforts to reduce prenatal alcohol exposure (PAE), 11.7% of pregnant women in the U.S. consume alcohol and 3.9% binge drink. PAE can lead to growth retardation, facial dysmorphology and neurobehavioral disabilities, the key manifestations of Fetal Alcohol Spectrum Disorders (FASD). Although the growth deficits correlate with the cognitive and behavioral impairments, we lack mechanistic insight into the basis for these growth deficits. A major driver of fetal growth deficits is maternal metabolic disruption, and although alcohol is well-known to alter metabolism, surprisingly, this has been minimally investigated in PAE. My preliminary data address this knowledge gap, and show that alcohol reduces maternal-fetal glucose pools, with commensurate rise in fetal amino acid catabolites including urea. Although alcohol stimulates skeletal muscle catabolism, I find no sign that this happens in alcohol-exposed dams. Instead, my preliminary studies find that alcohol-exposed dams fail to undergo an expected adaptation to an insulin-resistant state. Moreover, I find that alcohol-driven changes in maternal fasting glucose and insulin correlate with the alcohol-mediated reductions in fetal body and brain weight. Launching from these data, this proposal uses an established mouse model of PAE and tests the hypothesis that alcohol prevents the dam from entering an insulin-resistant state, thus limiting fetal glucose availability, and thereby increasing fetal reliance on amino acids to support gluconeogenesis instead of growth. The first phase of the K99 portion quantifies maternal-fetal fed/fasted glucose levels, gluconeogenesis, and their related metabolite pools to understand how alcohol alters maternal-fetal energetics to reduce fetal glucose availability. The second phase of the K99 portion quantifies insulin signaling, and glucose storage and utilization in maternal liver, to test the hypothesis that alcohol prevents maternal adaptation to insulin resistance. Finally, the R00 phase will identify the underlying mechanism(s) that mediates this adaptive failure in alcohol-exposed dams, focusing on major candidate drivers including leptin-resistance, and prolactin and placental lactogen activity. Future studies will test these candidates functionally using organ-targeted transgenic and knockout mouse models. I will be trained in the methodologies of whole-animal and cellular metabolic assessment and an in-depth understanding of insulin/leptin signaling in pregnancy. I will also be trained in mouse behavioral assessment, looking toward future studies of how these metabolic changes may impact cognitive function. This work provides novel, mechanistic insight into the basis for the fetal growth deficits that typify FASD, focusing on key, heretofore overlooked metabolic processes. These data may also inform the development of a metabolite fingerprint or hormone test to identify at-risk pregnancies, and they will offer insights into nutrient-based interventions that could improve gestational outcomes in those pregnancies.

项目概要 尽管公共卫生部门努力减少产前酒精暴露 (PAE)，但美国仍有 11.7% 的孕妇饮酒。 饮酒和酗酒3.9%。 PAE 可导致生长迟缓、面部畸形和 神经行为障碍是胎儿酒精谱系障碍 (FASD) 的主要表现。虽然 生长缺陷与认知和行为障碍相关，我们缺乏对其机制的了解 这些增长赤字的基础。胎儿生长缺陷的一个主要驱动因素是母体代谢紊乱，并且 尽管众所周知，酒精会改变新陈代谢，但令人惊讶的是，PAE 中对此的研究却很少。 我的初步数据解决了这一知识差距，并表明酒精会降低母胎血糖池， 胎儿氨基酸分解代谢物（包括尿素）相应增加。虽然酒精会刺激骨骼 肌肉分解代谢，我没有发现任何迹象表明这种情况发生在暴露于酒精的母鼠身上。相反，我的初步研究 发现暴露于酒精的母鼠无法对胰岛素抵抗状态进行预期的适应。而且，我 发现酒精驱动的母亲空腹血糖和胰岛素变化与酒精介导的 胎儿身体和大脑重量减少。从这些数据出发，该提案使用既定的鼠标 PAE 模型并检验酒精阻止母鼠进入胰岛素抵抗状态的假设 状态，从而限制胎儿葡萄糖的可用性，从而增加胎儿对氨基酸的依赖 支持糖异生而不是生长。 K99部分第一阶段量化母胎 餐后/空腹血糖水平、糖异生及其相关代谢物库，以了解酒精如何改变 母胎能量学以减少胎儿葡萄糖的可用性。第二期K99部分量化 胰岛素信号传导以及母体肝脏中葡萄糖的储存和利用，以检验酒精 阻止母亲适应胰岛素抵抗。最后，R00阶段将识别底层 调解酒精暴露水坝中这种适应性失效的机制，重点关注主要候选者 驱动因素包括瘦素抵抗、催乳素和胎盘催乳素活性。未来的研究将测试这些 候选人功能性地使用器官靶向转基因和基因敲除小鼠模型。我将接受以下方面的培训 全动物和细胞代谢评估的方法以及对 怀孕期间的胰岛素/瘦素信号传导。我还将接受小鼠行为评估方面的培训，期待 未来研究这些代谢变化如何影响认知功能。这部作品提供了新颖、 对 FASD 典型胎儿生长缺陷基础的机制洞察，重点关注迄今为止的关键 忽视了新陈代谢过程。这些数据还可以为代谢物指纹的发展提供信息或 激素测试来识别高危妊娠，他们将提供基于营养的干预措施的见解， 可以改善这些妊娠的妊娠结局。