Prenatal alcohol exposure disrupts maternal-fetal iron metabolism in FASD

产前酒精暴露会扰乱 FASD 母胎铁代谢

• 批准号: 8857181
• 负责人: SUSAN M. SMITH
• 金额: $ 32.49万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857181
• 关键词: Address; Affect; Alcohols; BMP6 gene; Biochemistry; Brain; Clinical; Data; Development; Dietary Intervention; Ethanol; Ferritin; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Liver; Fetus; Health; Interleukin-1; Intervention; Iron; Knowledge; Liver; Micronutrients; Modeling; Mothers; Neurodevelopmental Disability; Nutrient; Nutritional; Nutritional Requirements; Oral; Organ; Outcome; Pathway interactions; Pregnancy; Production; Rattus; Reaction; Research; SHPS-1 protein; SLC11A2 gene; STAT3 gene; Signal Transduction; TNF gene; Techniques; Testing; Tissues; Transferrin; Transferrin Receptor; alcohol exposure; evidence base; fetal; fetus nutrition; fundamental research; hepcidin; improved; iron deficiency; iron metabolism; iron supplement; metal transporting protein 1; micronutrient deficiency; monoamine; neurobehavioral; offspring; placental transfer; prevent; public health relevance; research study; response; uptake

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.

描述（由申请人提供）：胎儿酒精谱系（FASD）是神经发育障碍的主要原因。我们和其他人最近表明，妊娠，孕产妇缺乏症（ID）的最常见的微量营养素缺乏，大大提高了后代对酒精损害的脆弱性，包括神经行为和神经解剖学成果。该提案调查了这种酒精铁相互作用的机制。具体而言，我们通过乙醇对乙醇的肝素失调，检验了产前乙醇暴露（PAE）的假设阻碍了从母亲到胎儿到胎儿大脑的铁的流动。这种肝素失调会阻碍胎儿铁的吸收，因此PAE会恶化胎儿铁的状态，尤其是在胎儿大脑中。使用PAE的大鼠模型，我们将记录PAE对胎儿和母铁含量，关键铁依赖性活性的影响，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。我们将使用铁补充形式来测试铁补充剂是否可以使胎儿脑铁的含量和脑铁含量和脑活动具有已知敏感性，并使用铁补充剂形式，这些形式用于甲基肝素不良的条件。我们的初步数据支持这一假设，并表明PAE严重破坏了从母亲到胎儿到胎儿大脑的铁流。我们发现，在PAE下，胎儿肝脏以胎儿大脑为代价保留铁，即使母亲的铁不足（IS），胎儿大脑也会变得缺乏铁（ID）。如果母亲是ID，则乙醇会加剧这种肝脑断开连接，并防止适应，否则可以增强胎儿铁的吸收。由于铁对于健康的脑发育至关重要，因此乙醇对胎儿铁代谢的破坏可能解释了为什么ID放大了乙醇的神经发育损害。关于PAE如何影响胎儿和孕产妇的营养利用以及这种变化如何影响妊娠结局，知之甚少。鉴于已经进行了临床干预措施，以测试包括铁在内的微量营养素补充剂是否会减少对FASD的脆弱性，因此必须了解PAE的基本生物化学基本生物化学的基本生物化学，因此PAE如何改变营养需求。这项基本研究对于制定有效的，基于证据的饮食干预措施至关重要，从而减少胎儿对FASD的脆弱性。