Prenatal Alcohol Exposure Dysregulates Fetal Iron Homeostasis

描述（由申请人提供）：产前酒精暴露（PAE）导致与胎儿酒精谱系障碍（FASD）相关的显著神经元丧失和许多认知和行为缺陷。微量元素铁是神经发育的重要调节剂；妊娠期铁过量和铁缺乏（ID）都会导致神经变性和行为缺陷。许多基本的细胞代谢过程都需要铁，但当铁过量时，它是一种有效的促氧化剂。因此，铁稳态必须在系统和细胞水平上严格调节。酒精暴露会解除对铁代谢的这种严格的体内平衡控制。在“正常”铁摄入量下，酒精会增强肠道对铁的吸收和肝脏对铁的沉积，导致铁过载，从而加剧肝损伤。在缺铁的情况下，PAE期间缺铁会放大酒精引起的小脑神经变性和联想学习缺陷。因此，酒精扭曲了铁的体内平衡，这种失调加剧了酒精引起的组织损伤。本研究在分子和细胞水平上研究了酒精在PAE妊娠中破坏铁稳态并对大脑发育产生不利影响的机制。我将使用妊娠期暴饮暴露的大鼠模型，研究在三种母体铁状态（正常、缺乏和过量）下，酒精是如何调节铁在胎儿体内的输送和功能的。研究1A和1B评估了酒精对母体和胎儿室中控制组织和细胞铁代谢的分子信号的影响。研究2评估了这种失调对神经发育过程中能量产生所必需的铁依赖性反应的后果。这项工作将提供一个全面的了解酒精是如何在怀孕期间扰乱铁稳态并导致FASD的神经发育缺陷的。由于酒精滥用通常被掩盖，并且存在通过补充摄入过量铁或未确诊缺铁的孕妇队列，因此在我们试图通过膳食铁补充剂改善FASD结果之前，有必要了解酒精是如何调节母体和胎儿铁命运和组织损伤风险的。

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.