Mediating and Moderating Effects of Fetal Alcohol-Related Iron Deficiency in FASD

胎儿酒精相关缺铁对胎儿酒精谱系障碍 (FASD) 的介导和调节作用

基本信息

批准号：
8798553
负责人：
ROBERT COLIN CARTER
金额：
$ 18.51万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-05 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8798553
关键词：
Affect Age Alcohol consumption Alcoholic beverage heavy drinker Alcohols Anemia Animals Biological Markers Carrier Proteins Cognitive deficits Cohort Studies Congenital Abnormality Data Development Diet Disease Drug usage Ethanol Exposure to Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal alcohol effects Fetus Functional disorder Gene Expression Gestational Age Goals Growth Heavy Drinking Homeostasis Human Incidence Infant Intervention Iron Iron deficiency anemia Knowledge Lead Life Light Link Mediating Mental Retardation Modeling Mothers National Institute on Alcohol Abuse and Alcoholism Nervous System Physiology Newborn Infant Nutrient Outcome Pathologist Pathology Pattern Physiology Placenta Population Population Study Positioning Attribute Postpartum Period Pregnancy Pregnant Women Prevalence Preventive Intervention Public Health Rattus Recruitment Activity Research Research Infrastructure Research Personnel Sampling Site Smoking Status Staging Strategic Planning Structural defect Structure Testing Therapeutic Intervention Time Work alcohol consumption during pregnancy alcohol exposure behavioral outcome binge drinking body system cohort fetal human subject infancy innovation iron deficiency meetings neurobehavioral novel offspring placental transfer prenatal prospective protein expression public health relevance

项目摘要

DESCRIPTION (provided by applicant): Human and animal studies have shown that fetal alcohol exposure increases the incidence of iron deficiency in infancy. Fetal alcohol-related infant iron deficiency is of particular importance in fetal alcohol spectrum disorders (FASD) because it may serve as a mediating mechanism by which alcohol exposure disrupts normal development. Moreover, iron deficiency has been shown to exacerbate the effects of fetal alcohol exposure on growth and neurologic function. In a prospective, longitudinal cohort study, we found that maternal binge drinking was associated with a 70% increase in prevalence of iron deficiency anemia (IDA) at age 6.5 mo. We also found that infants with IDA were markedly more vulnerable to effects of fetal alcohol on growth. Moreover, alcohol exposure and iron status have been shown to affect growth and behavioral outcomes synergistically in a rat model and to affect similar outcomes in humans. The objective of our study is to identify the mechanisms by which fetal alcohol exposure disrupts fetal iron stores and consequently leads to growth and cognitive deficits. Our preliminary data suggest that that the prenatal alcohol-related increase in IDA is due to a reduction in fetal iron stores resulting from disrupted placental iron transfer. We hypothesize that fetal alcohol exposure disrupts placental iron transfer from mother to fetus via two mechanisms: (a) alterations in placental structure that impede transfer of iron to the fetus and (b) altered expression of iron transport proteins, leading to disruption of cellular transplacental iron transport. In the proposed study, we aim to test this hypothesis and to examine the degree to which alcohol-related iron deficiency mediates and/or moderates fetal alcohol effects on somatic growth and neurobehavioral outcomes. We will recruit 90 pregnant women to provide a final sample of 60 mothers-30 heavy drinkers, 30 abstainer/light drinkers-and their infants, we will obtain prospective data on maternal alcohol consumption, diet, and biomarkers of iron status three times during pregnancy, placental samples at delivery, biomarkers of infant iron status at 2 wk and 6.5 mo, and neurobehavioral outcomes at 6.5 mo. First, we will examine the relation of fetal alcohol exposure to (1) placental structural abnormalities that impede nutrient transfer from mother to fetus and (2) alterations in placental iron transport protein expression. Next, we will determine the degree to which alcohol-related placental structural abnormalities and/or disrupted cellular transplacental iron transport mediate effects of fetal alcohol exposure on accretion of fetal iron stores, adjusting for other factors known to affect placental function and iron status, such as maternal iron status, smoking, and other drug use and gestational age at delivery. We will then determine the degree to which diminished fetal iron stores mediate and/or moderate the effects of prenatal alcohol exposure on growth and neurobehavioral function at 6.5 mo postpartum. This study provides an unusual opportunity to test a mechanistic hypothesis regarding the development of FASD directly in human subjects. Identification of mechanisms through which fetal alcohol-related infant iron deficiency mediates developmental sequelae of prenatal alcohol exposure has the potential to transform how we conceptualize the neuropathologic consequences of fetal alcohol exposure. It will also provide foundational knowledge for the NIAAA Strategic Plan for Research goal to "use the knowledge gained in uncovering target sites for ethanol's action," such as iron homeostasis, "to begin the development of potential therapeutic or preventive interventions" for FASD.

描述（由申请人提供）：人类和动物研究表明，胎儿酒精暴露会增加婴儿期铁缺乏症的发生率。胎儿酒精相关的婴儿缺乏症在胎儿酒精谱系（FASD）中尤其重要，因为它可能是一种介导机制，通过这种机制，酒精暴露会破坏正常发育。此外，已经证明铁缺乏症加剧了胎儿酒精暴露对生长和神经功能功能的影响。在一项前瞻性的纵向队列研究中，我们发现孕产妇的暴饮暴食与6.5 mo的铁缺乏症患病率增加了70％。我们还发现，患有IDA的婴儿更容易受到胎儿酒精对生长的影响。此外，酒精暴露和铁状态已被证明会在大鼠模型中协同影响生长和行为结果，并影响人类的相似结果。我们研究的目的是确定胎儿酒精暴露破坏胎儿铁储存的机制，从而导致生长和认知缺陷。我们的初步数据表明，产前酒精相关的增加 IDA是由于胎盘转移中断导致的胎儿铁储存量的减少所致。我们假设胎儿酒精暴露通过两种机制破坏了从母亲到胎儿的胎盘铁的转移：（a）胎盘结构的改变，阻碍铁转移到胎儿，（b）改变铁转运蛋白的表达，导致细胞移植铁的破坏。在拟议的研究中，我们旨在检验这一假设，并研究与酒精相关的铁缺乏症的介导和/或调节性胎儿酒精对体细胞生长和神经行为结果的影响。 We will recruit 90 pregnant women to provide a final sample of 60 mothers-30 heavy drinkers, 30 abstainer/light drinkers-and their infants, we will obtain prospective data on maternal alcohol consumption, diet, and biomarkers of iron status three times during pregnancy, placental samples at delivery, biomarkers of infant iron status at 2 wk and 6.5 mo, and neurobehavioral outcomes at 6.5 mo.首先，我们将研究胎儿酒精暴露于（1）胎盘结构异常，这些异常阻碍了从母亲到胎儿的营养转移以及（2）胎盘铁转运蛋白表达的改变。接下来，我们将确定与酒精相关的胎盘结构异常和/或破坏的细胞移植铁转运介导胎儿酒精暴露对胎儿铁储存的增生的影响，从而调整已知影响胎盘功能和铁状态的其他因素，例如母体铁状态，吸烟以及其他药物的使用以及其他药物使用年龄，以及交货时的其他因素。然后，我们将确定胎儿铁储存的程度介导和/或减少产前酒精暴露对产后6.5 mo的生长和神经行为功能的影响。这项研究提供了一个异常的机会，可以直接在人类受试者中直接检验有关FASD发展的机理假设。鉴定胎儿酒精相关的婴儿缺乏症可以介导产前酒精暴露的发育后遗症的机制，有可能改变我们如何概念化胎儿酒精暴露的神经病理学后果。它还将为NIAAA战略计划提供研究目标的基本知识，以“利用在发现乙醇行动的目标站点中获得的知识，例如铁稳态，以开始开发FASD的潜在治疗或预防性干预措施”。