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）相关的显著神经元丢失和许多认知和行为缺陷。微量营养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需要铁，但它是一个强大的促氧化剂时，过量存在。因此，铁稳态必须在系统和细胞水平上严格调节。酒精暴露解除了这种对铁代谢的严格稳态控制。在“正常”铁摄入量下，酒精会增强铁的肠道吸收和肝脏沉积，导致铁超负荷状态，加剧肝损伤。在缺乏铁的情况下，PAE期间铁的缺乏放大了酒精诱导的小脑神经变性和联合学习缺陷。因此，酒精扭曲了铁的体内平衡，这种失调增强了酒精引起的组织损伤。这项建议调查，在分子和细胞水平上，酒精破坏铁稳态的PAE怀孕和不利影响大脑发育的机制。我将使用妊娠期酒精暴露的大鼠模型，并研究在三种母体铁状态（正常、缺乏和过量）下，酒精如何失调胎儿体内的铁输送和功能。研究1A和1B评估了酒精对控制母体和胎儿室中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如何扰乱铁稳态在怀孕期间，并有助于FASD的神经发育缺陷。由于酒精滥用往往被掩盖，并且存在通过补充剂获得过量铁或患有未诊断的铁缺乏症的孕妇队列，因此在我们尝试通过膳食铁补充剂改善FASD结局之前，了解酒精如何失调母体和胎儿铁命运以及组织损伤风险至关重要。

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.