Mediating and Moderating Effects of Fetal Alcohol-Related Iron Deficiency in 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)中特别重要，因为它可能是酒精暴露扰乱正常发育的一种中介机制。此外，铁缺乏已被证明加剧了胎儿酒精暴露对生长和神经功能的影响。在一项前瞻性的纵向队列研究中，我们发现，在6.5mo时，母亲酗酒与缺铁性贫血(IDA)患病率增加70%相关。我们还发现，患有IDA的婴儿明显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在大鼠模型中协同影响生长和行为结果，并在人类中影响类似的结果。我们研究的目的是确定胎儿酒精暴露扰乱胎儿铁储存从而导致生长和认知缺陷的机制。我们的初步数据表明，产前饮酒相关的增加 IDA是由于胎盘铁转移中断导致胎儿铁储存减少所致。我们 假设胎儿酒精暴露通过两种机制扰乱胎盘铁从母亲到胎儿的转移：(A)胎盘结构的改变，阻碍铁向胎儿的转移；(B)铁运输蛋白的表达改变，导致细胞通过胎盘的铁运输中断。在拟议的研究中，我们的目标是检验这一假设，并检查与酒精相关的铁缺乏在多大程度上中介和/或缓和胎儿酒精对身体生长和神经行为结果的影响。我们将招募90名孕妇提供60名母亲-30名重度饮酒者，30名禁酒者/少量饮酒者-及其婴儿的最终样本，我们将获得孕妇在怀孕期间三次饮酒、饮食和铁状况生物标志物的前瞻性数据，分娩时胎盘样本，婴儿铁状况生物标志物在2周和6.5月，以及6.5mo神经行为结果。首先，我们将研究胎儿酒精暴露与(1)阻碍母亲向胎儿转移营养的胎盘结构异常和(2)胎盘铁转运蛋白表达的变化的关系。接下来，我们将确定酒精相关的胎盘结构异常和/或细胞经胎盘铁运输中断的程度，以调整其他已知影响胎盘功能和铁状态的因素，如母亲铁状况、吸烟和其他药物使用和分娩时的孕周。然后，我们将确定胎儿铁储存减少在多大程度上中介和/或缓和了产前酒精暴露对产后6.5个月的生长和神经行为功能的影响。这项研究提供了一个不同寻常的机会，可以直接在人类受试者中检验关于FASD发展的机制假说。识别胎儿酒精相关的婴儿铁缺乏介导产前酒精暴露的发育后遗症的机制，有可能改变我们对胎儿酒精暴露的神经病理后果的概念化。它还将为NIAAA的研究战略计划提供基础知识，目标是“利用在发现乙醇作用的目标部位所获得的知识”，例如铁稳态，“开始开发潜在的治疗或预防干预措施”。

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.