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: 9379245
• 负责人: PAMELA J KLING
• 金额: $ 31.87万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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/9379245
• 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; HFE2 gene; 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; TFRC gene; TNF gene; Techniques; Testing; Tissues; Transferrin; 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）：胎儿酒精谱系障碍（FASD）是神经发育障碍的主要原因。我们和其他人最近表明，怀孕最常见的微量营养素缺乏症，母亲缺铁（ID），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结果。该建议探讨了这种酒精-铁相互作用的机制。具体来说，我们测试的假设，产前乙醇暴露（PAE）阻碍铁从母亲到胎儿胎儿的胎儿大脑的流动，通过乙醇的铁调素的失调。这种铁调素失调阻碍胎儿铁摄取，因此PAE影响胎儿铁状态，尤其是胎儿脑中的铁状态。使用大鼠PAE模型，我们将记录PAE对胎儿和母体铁含量的影响，关键的铁依赖性活动，以及控制铁吸收和利用的蛋白质和调控信号的表达和活性。我们将进一步测试铁补充剂是否可以使胎儿脑铁含量和脑活动正常化，已知对铁-酒精相互作用的敏感性，使用临床上用于铁调素失调的条件的铁补充剂形式。我们的初步数据支持这一假设，并表明PAE显着扰乱铁从母亲到胎儿到胎儿大脑的流动。我们发现，在PAE下，胎儿肝脏以牺牲胎儿大脑为代价保留铁，即使母亲铁充足（IS），胎儿大脑也会出现铁缺乏（ID）。如果母亲是ID，乙醇会消除这种肝-脑断开，并防止适应，否则会增加胎儿铁的吸收。因为铁对健康的大脑发育是必不可少的，乙醇对胎儿铁代谢的破坏可以解释为什么ID放大了乙醇对神经发育的损害。关于PAE如何影响胎儿和母体的营养利用，以及这些变化如何影响妊娠结局，我们知之甚少。鉴于临床干预已经在进行中，以测试包括铁在内的微量营养素补充剂是否会降低对FASD的脆弱性，因此必须了解PAE利用微量营养素的基本生物化学，以及PAE如何改变营养需求。这项基础研究对于开发有效的、基于证据的饮食干预措施，减少胎儿对FASD的脆弱性至关重要。