Outcome of Neurological Disorders in Adults Exposed to Moderate Levels of Alcohol in Utero

子宫内接触适量酒精的成人神经系统疾病的结果

• 批准号: 10655859
• 负责人: Surojit Paul
• 金额: $ 41.13万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655859
• 关键词: Address; Adult; Adult Children; Adverse effects; Affect; Age; Alcohol abuse; Alcoholism; Alcohols; Antioxidants; Attenuated; Behavioral; Biochemical; Blood alcohol level measurement; Brain; Brain Diseases; Brain Injuries; Brain region; CX3CL1 gene; Characteristics; Child; Chronic; Clinical; Cognitive; Communication; Compensation; Consumption; Control Groups; Country; Craniofacial Abnormalities; Data; Dimerization; Dinoprostone; Disease; Electron Spin Resonance Spectroscopy; Etiology; Evaluation; Exposure to; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetal Development; Fetus; Flow Cytometry; Generations; Glutathione; Glutathione Metabolism Pathway; Growth; Health; Homeostasis; Imaging Techniques; Impairment; Infarction; Inflammatory; Inflammatory Response; International; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knockout Mice; Knowledge; Life; Link; Longevity; Magnetic Resonance Imaging; Middle Cerebral Artery Occlusion; Mission; Molecular; Mus; Neuroimmune; Neurologic; Neurological outcome; Neurons; Neuroprotective Agents; Newborn Infant; Outcome; Oxidative Stress; Pattern; Peptides; Peripheral; Pharmacology Study; Predisposition; Pregnancy; Pregnant Women; Premature Mortality; Prostaglandins; Protein Tyrosine Phosphatase; Public Health; Reactive Oxygen Species; Recommendation; Research; Risk; Severities; Signal Pathway; Signal Transduction; System; Testing; Up-Regulation; aged; alcohol consumption during pregnancy; alcohol measurement; behavior test; binge drinking; chemokine; disability; drinking; excitotoxicity; experimental study; functional outcomes; glial activation; immune cell infiltrate; in utero; loss of function; male; maternal alcohol use; middle age; mouse model; nervous system disorder; neurobehavioral; neurodevelopment; neuroprotection; novel; offspring; peptidomimetics; prenatal exposure; programs; restoration; sex; social

Project Summary / Abstract Heavy maternal alcohol consumption during pregnancy is known to interfere with normal fetal development and is the leading cause of disabilities and premature mortality in children. On the other hand, moderate level of maternal alcohol consumption (blood alcohol concentration < 0.08%) is thought to be less disruptive to neurodevelopment. However, it is still unclear whether such moderate prenatal alcohol exposure (PAE) has any adverse effect on the brain function of the adult offspring. Our preliminary data now indicate that moderate PAE could lead to depletion of endogenous glutathione (GSH) level in the brain of the adult mice offspring and also diminish the function of a brain-enriched and neuron-specific tyrosine phosphatase, STEP that has been shown to be involved in neuroprotection against excitotoxic insults. The preliminary data also provide compelling evidence that a mild ischemic insult in adult PAE offspring leads to exacerbation of ischemic brain injury and is associated with up regulation of inflammatory response in the brain. These findings raise the possibility that moderate PAE has a life-long impact on the antioxidant defense system in the brain of the offspring. The resulting higher basal level of oxidative stress could compromise the ability of the brain to compensate when exposed to a neurological insult in later stages of life leading to augmentation of brain damage. To test this novel hypothesis, in Aim 1 we propose to evaluate the impact of moderate PAE on the synthesis and turnover of GSH, generation of reactive oxygen species and function of STEP in different brain regions of adult, middle-aged and aged PAE mice offspring. Our approach will include the non-invasive Electron Paramagnetic Resonance (EPR) imaging technique and a multitude of molecular and biochemical studies, utilizing both male and female PAE offspring with age-matched non-PAE control group. The proposed studies in Aim 2 will utilize magnetic resonance imaging (MRI) and a battery of behavioral tests for noninvasive and longitudinal evaluation of the progression and severity of ischemic brain damage in adult and aged PAE mice offspring from both sexes. These studies will further evaluate whether loss of function of STEP could contribute to the exacerbation of ischemic brain injury in PAE offspring. At the molecular level, the proposed studies in Aim 3 will further delineate the causal link between the high basal level of oxidative stress and exacerbation of ischemic brain injury in both male and female PAE offspring. Our approach will utilize flow cytometry, quantitative PCR, immunohistochemical and pharmacological studies, as well as multiple knockout mice. The proposed research is significant since it will addresse a significant gap in our knowledge on the life-long health risks of moderate alcohol consumption during pregnancy.

项目概要/摘要 众所周知，怀孕期间孕妇大量饮酒会干扰胎儿的正常发育， 是儿童残疾和过早死亡的主要原因。另一方面，中等水平 产妇饮酒（血液酒精浓度 < 0.08%）被认为对胎儿的干扰较小 神经发育。然而，目前尚不清楚这种中等程度的产前酒精暴露（PAE）是否有任何影响。 对成年后代的大脑功能产生不良影响。我们的初步数据现在表明中等 PAE 可能会导致成年小鼠后代大脑中内源性谷胱甘肽（GSH）水平的消耗，并且 削弱大脑丰富的神经元特异性酪氨酸磷酸酶（STEP）的功能 参与针对兴奋性毒性损伤的神经保护。初步数据也提供了令人信服的信息 有证据表明，成年 PAE 后代的轻度缺血性损伤会导致缺血性脑损伤加剧，并且 与大脑炎症反应的上调有关。这些发现提出了这样的可能性： 中等程度的 PAE 对后代大脑中的抗氧化防御系统具有终生影响。由此产生的 较高的氧化应激基础水平可能会损害大脑在暴露于环境时的补偿能力 生命后期的神经损伤，导致脑损伤加剧。为了检验这个新颖的假设， 在目标 1 中，我们建议评估适度的 PAE 对 GSH 的合成和周转的影响，生成 成人、中年和老年PAE不同脑区活性氧含量及STEP功能 老鼠的后代。我们的方法将包括非侵入性电子顺磁共振 (EPR) 成像 技术和大量的分子和生物化学研究，利用雄性和雌性 PAE 后代 与年龄匹配的非 PAE 对照组。目标 2 中拟议的研究将利用磁共振成像 （MRI）和一系列行为测试，用于无创和纵向评估进展和严重程度 成年和老年 PAE 小鼠后代的缺血性脑损伤的研究。这些研究将进一步 评估 STEP 功能丧失是否会导致 PAE 中缺血性脑损伤的恶化 后代。在分子水平上，目标 3 中提出的研究将进一步描述两者之间的因果关系。 男性和女性 PAE 中氧化应激基础水平较高且缺血性脑损伤加剧 后代。我们的方法将利用流式细胞术、定量 PCR、免疫组织化学和药理学 研究以及多个基因敲除小鼠。拟议的研究意义重大，因为它将解决一个重要问题 我们对怀孕期间适度饮酒对终生健康风险的认识存在差距。