Prenatal Alcohol Exposure Dysregulates Fetal Iron Homeostasis

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DESCRIPTION (provided by applicant): Prenatal Alcohol Exposure (PAE) causes significant neuronal loss and numerous cognitive and behavioral deficits associated with Fetal Alcohol Spectrum Disorders (FASD). An important modulator of neurodevelopment is the micronutrient iron; gestational iron excess and iron deficiency (ID) both cause neurodegeneration and behavioral deficits. Many essential cellular metabolic processes require iron, yet it is a potent pro-oxidant when present in excess. Thus iron homeostasis must be tightly regulated at both the systemic and cellular levels. Alcohol exposure deregulates this tight homeostatic control of iron metabolism. Under "normal" iron intakes alcohol enhances the intestinal absorption and liver deposition of iron, resulting in an iron overload status that exacerbates liver injury. Under deficiency, the lack of iron during PAE magnifies alcohol-induced cerebellar neurodegeneration and associative learning deficits. Hence, alcohol distorts iron homeostasis, and this dysregulation enhances alcohol-induced tissue damage. This proposal investigates, at the molecular and cellular level, the mechanism by which alcohol disrupts iron homeostasis in the PAE pregnancy and adversely affects brain development. I will use a rat model of gestational binge alcohol exposure and investigate how alcohol dysregulates iron delivery and function within the fetus under three maternal iron states (normalcy, deficiency, and excess). Studies 1A and 1B evaluate alcohol's effects on molecular signals that govern tissue and cellular iron metabolism in the maternal and fetal compartments. Study 2 evaluates the consequences of this dysregulation to iron-dependent reactions essential for energy production during neurodevelopment. This work will provide a comprehensive understanding of how alcohol perturbs iron homeostasis during pregnancy and contributes to the neurodevelopmental deficits of FASD. Because alcohol abuse is often masked and cohorts of pregnant women exist that receive excess iron through supplementation or have undiagnosed iron deficiency, it is essential to understand how alcohol dysregulates maternal and fetal iron fate and risk for tissue injury before we attempt to improve FASD outcomes with dietary iron supplements.