Prenatal alcohol exposure disrupts maternal-fetal iron metabolism in FASD

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DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorders (FASD) are a leading cause of neurodevelopmental disability. We and others recently showed that the most common micronutrient deficiency of pregnancy, maternal iron deficiency (ID), substantially heightens the offspring's vulnerability to alcohol's damage, including neurobehavioral and neuroanatomical outcomes. This proposal investigates the mechanism underlying this alcohol-iron interaction. Specifically, we test the hypothesis that prenatal ethanol exposure (PAE) impedes the flow of iron from mother to fetus to fetal brain, through ethanol's dysregulation of hepcidin. This hepcidin dysregulation impedes fetal iron uptake and thus PAE worsens fetal iron status and especially in fetal brain. Using a rat model of PAE, we will document PAE's impact upon fetal and maternal iron content, key iron-dependent activities, and the expression and activity of proteins and regulatory signals that control iron uptake and utilization. We will furthr test whether iron supplements can normalize fetal brain iron content and brain activities with known sensitivity to iron-alcohol interactions, using iron supplement forms that are used clinically for conditions where hepcidin is dysregulated. Our preliminary data support this hypothesis and show that PAE significantly disrupts iron flow from mother to fetus to fetal brain. We find that under PAE, fetal liver retains iron at the expense of fetal brain, and fetal brain becomes iron-deficient (ID) even though the mother is iron-sufficient (IS). If the mother is ID, ethanol worsens this liver-brain disconnect and prevents adaptations that would otherwise enhance fetal iron uptake. Because iron is essential for healthy brain development, ethanol's disruption of fetal iron metabolism may explain why ID magnifies ethanol's neurodevelopmental damage. Little is known about how PAE affects fetal and maternal nutrient utilization, and how such changes impact gestational outcome. Given that a clinical intervention is already underway to test if micronutrient supplements including iron will reduce vulnerability to FASD, it is essential to understand the basic biochemistry underlying micronutrient utilization by PAE and, thus, how PAE might change nutrient requirements. This fundamental research is crucial to develop effective, evidence-based dietary interventions that reduce fetal vulnerability to FASD.