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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缺铁的发生率。胎儿酒精相关的婴儿铁缺乏在胎儿酒精谱系障碍（FASD）中尤为重要，因为它可能作为酒精暴露破坏正常发育的中介机制。此外，缺铁已被证明会加剧胎儿酒精暴露对生长和神经功能的影响。在一项前瞻性纵向队列研究中，我们发现，母亲酗酒与6.5月龄缺铁性贫血（IDA）患病率增加70%相关。我们还发现，患有缺铁性贫血的婴儿明显更容易受到胎儿酒精对生长的影响。此外，在大鼠模型中，酒精暴露和铁状态已被证明协同影响生长和行为结果，并影响人类的类似结果。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