Prenatal alcohol exposure disrupts maternal-fetal iron metabolism in FASD

描述(由申请人提供)：胎儿酒精谱系障碍(FASD)是导致神经发育障碍的主要原因。我们和其他人最近表明，妊娠最常见的微量营养素缺乏症--母体缺铁(ID)--极大地增加了后代对酒精损害的脆弱性，包括神经行为和神经解剖学结果。这项提议研究了酒精-铁相互作用的机制。具体地说，我们测试了这样一种假设，即产前酒精暴露(PAE)通过乙醇对海普西丁的失调调节，阻碍了铁从母亲到胎儿到胎儿大脑的流动。这种海普西丁的失调阻碍了胎儿的铁摄取，因此PAE恶化了胎儿的铁状况，尤其是在胎儿的大脑中。使用PAE的大鼠模型，我们将记录PAE对胎儿和母亲铁含量的影响，关键的铁依赖活动，以及控制铁吸收和利用的蛋白质和调节信号的表达和活性。我们将进一步测试铁补充剂是否可以使已知对铁-酒精相互作用敏感的胎儿大脑铁含量和大脑活动正常化，使用临床上使用的铁补充剂形式来治疗海普西丁失调的情况。我们的初步数据支持这一假设，并表明PAE显著扰乱了从母亲到胎儿到胎儿大脑的铁流动。我们发现，在PAE下，胎儿肝脏以牺牲胎儿大脑为代价保留铁，而胎儿大脑变得缺铁(ID)，即使母亲铁充足(IS)。如果母亲是ID，乙醇会加剧这种肝脏和大脑的脱节，并阻止适应，否则会增加胎儿的铁摄取。由于铁对大脑的健康发育是必不可少的，乙醇对胎儿铁代谢的干扰可能解释了为什么ID放大了乙醇对神经发育的损害。关于PAE如何影响胎儿和母亲的营养利用，以及这种变化如何影响妊娠结局，人们知之甚少。鉴于临床干预措施已经在进行，以测试包括铁在内的微量营养素补充剂是否会降低FASD的易感性，因此必须了解PAE利用微量营养素的基本生物化学，从而了解PAE可能如何改变营养需求。这项基础研究对于开发有效的、循证的饮食干预措施，降低胎儿对FASD的易感性至关重要。

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.