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.