Prenatal Alcohol Exposure Dysregulates Fetal Iron Homeostasis

描述(由申请人提供)：产前酒精暴露(PAE)会导致与胎儿酒精谱系障碍(FASD)相关的大量神经元丢失和许多认知和行为缺陷。神经发育的一个重要调节因子是微量营养素铁；妊娠期铁过量和铁缺乏(ID)都会导致神经退化和行为缺陷。许多重要的细胞代谢过程需要铁，但当铁过量存在时，它是一种强有力的促氧化剂。因此，必须在系统和细胞水平上严格控制铁的动态平衡。酒精暴露解除了对铁代谢的这种严格的动态平衡控制。在“正常”的铁摄入量下，酒精会促进肠道对铁的吸收和肝脏铁的沉积，导致铁超载状态，从而加剧肝脏损伤。在缺乏的情况下，PAE过程中铁的缺乏放大了酒精诱导的小脑神经变性和关联性学习障碍。因此，酒精扭曲了铁的稳态，这种失调加剧了酒精引起的组织损伤。这项建议从分子和细胞水平研究酒精扰乱PAE妊娠期间铁稳态并对大脑发育产生不利影响的机制。我将使用孕期酗酒暴露的大鼠模型，研究酒精如何在三种母体铁状态(正常、缺乏和过剩)下调节胎儿体内的铁供应和功能。研究1A和1B评估了酒精对控制母体和胎儿体内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反应的影响。这项工作将全面了解酒精如何扰乱怀孕期间的铁平衡，并导致FASD的神经发育缺陷。由于酒精滥用通常是被掩盖的，而且存在通过补充铁剂获得过量铁或患有未诊断的铁缺乏症的孕妇队列，因此在我们试图通过膳食铁补充剂改善FASD结果之前，了解酒精如何失调母体和胎儿的铁命运以及组织损伤的风险是至关重要的。

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.