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

项目摘要/摘要 众所周知，怀孕期间大量饮酒会干扰胎儿的正常发育和 是导致儿童残疾和过早死亡的主要原因。另一方面，中等水平的 母亲饮酒(血液酒精浓度0.08%)被认为对 神经发育。然而，目前还不清楚这种适度的产前酒精暴露(PAE)是否有 对成年后代大脑功能的不利影响。我们的初步数据现在表明，适度的PAE 可导致成年小鼠子代脑内内源性谷胱甘肽(GSH)水平耗竭，还 削弱一种富含大脑和神经元特异性的酪氨酸磷酸酶的功能，这一步骤已经被证明 参与神经保护以抵御兴奋性毒性的侮辱。初步数据也令人信服 有证据表明，成年PAE子代的轻度缺血性损伤会导致缺血性脑损伤的加重，并且是 与大脑中炎症反应的上调有关。这些发现增加了这样一种可能性 适度的PAE会对后代大脑中的抗氧化防御系统产生终身影响。由此产生的 较高的基础氧化应激水平可能会损害大脑在暴露于空气中时的补偿能力 一种在生命后期导致大脑损伤加重的神经性侮辱。为了验证这一新的假设， 在目标1中，我们建议评估适度的PAE对GSH合成和周转的影响。 成人、中老年和老年PAE不同脑区活性氧种类及STEP功能的研究 老鼠的后代。我们的方法将包括无创电子顺磁共振(EPR)成像 技术和大量的分子和生化研究，利用雄性和雌性PAE后代 与年龄匹配的非PAE对照组。在AIM 2中提议的研究将利用核磁共振成像 (MRI)和一系列行为测试，用于无创性和纵向评估进展和严重程度 成年和老年PAE小鼠两性后代的缺血性脑损伤的研究。这些研究将进一步 评估STEP功能丧失是否可能导致PAE缺血性脑损伤的加重 后代。在分子水平上，目标3中拟议的研究将进一步描绘出 男性和女性PAE的高基础氧化应激水平和缺血性脑损伤的加重 后代。我们的方法将利用流式细胞术、定量聚合酶链式反应、免疫组织化学和药理学。 研究，以及多个基因敲除小鼠。拟议的研究具有重要意义，因为它将解决一个重要的 我们对怀孕期间适量饮酒对终身健康风险的认识存在差距。

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.