Is Maternal Iron Status a Risk Factor in Fetal Alcohol Syndrome?

描述(由申请人提供)：胎儿酒精谱系障碍(FASD)是导致智力低下的主要已知原因。它的严重性随着产次的增加而增加，这促使人们提出，产次会耗尽一些母性因素/S，否则酒精对胎儿的影响会减弱。虽然许多人推测这一因素是营养的，但这一假设在很大程度上仍未得到检验。我们假设，胎次因子/S反映了经常伴随酒精中毒的微量营养素缺乏。这项R21提案特别关注缺铁(ID)，这是孕妇最常见的营养缺乏症。妊娠ID会导致行为缺陷，与FASD的行为缺陷非常相似，这表明ID和酒精可能会协同作用，增强酒精的神经毒性。这项初步研究收集了支持这一假设的初步数据。我们将使用一个已建立的大鼠模型来验证这一假设，在该模型中，出生后早期酒精暴露扰乱了小脑神经元数量和小脑依赖学习。具体地说，我们将把铁充足(IS)或缺铁(ID)妊娠大鼠的后代从出生后第4天(P4)到P9暴露于酒精或对照溶液中，此后进行如下评估：目标1)在P10和P35，评估小脑种群的总体形态、细胞凋亡和增殖。皮质浦肯野细胞和深层间置神经元使用无偏向体视学进行定量；少突胶质细胞、星形胶质细胞和髓鞘含量使用免疫化学进行定量。用免疫印迹和免疫组织化学方法检测铁调节蛋白和铁反应蛋白的表达和分布，以介导GABA和谷氨酸能信号。我们预测，妊娠ID将加剧酒精对小脑种群的一个或多个影响，并且这种变化可能会持续到青春期。目的2)使用眨眼经典条件反射(ECC)在P32时测试小脑依赖学习；收集大脑用于AIM 1的P35组织学/体视学研究。由于控制ECC的神经回路以及酒精对其的影响已被很好地了解，我们可以直接将功能和细胞变化联系起来。我们预测ID将加重酒精引起的ECC损伤，支持母亲微量营养素状态调节酒精神经毒性的假设。微量营养素补充剂提供了廉价和简单的围产期干预措施，以减少酒精对胎儿的损害。这一目标直接符合NIAAA的使命，即识别和减少酒精引起的神经发育和神经行为障碍的原因。 与公共卫生相关：胎儿酒精综合征是已知的导致智力低下的主要原因。这项工作验证了营养因素可能加剧酒精对胎儿或婴儿影响的假设。它提出了这样一个概念，即营养干预可能会降低高危女性FASD的发病率。

DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorder (FASD) is the leading known cause of mental retardation. Its severity increases with parity, prompting suggestions that parity depletes some maternal factor/s that otherwise attenuate alcohol's effects on the fetus. While many speculate that this factor is nutritional, this hypothesis remains largely untested. We hypothesize that the parity factor/s reflect the micronutrient deficiencies that frequently accompany alcoholism. This R21 proposal focuses specifically on iron deficiency (ID), the most common nutrient deficiency in pregnant women. Gestational ID causes behavioral deficits that strongly parallel those of FASD, suggesting that ID and alcohol may synergize to heighten alcohol's neurotoxicity. This pilot study gathers preliminary data in support of this hypothesis. We will test this hypothesis using an established rat model in which early postnatal alcohol exposure disrupts cerebellar neuronal populations and cerebellum-dependent learning. Specifically, we will expose the offspring of iron-sufficient (IS) or ID pregnant rats to alcohol or control solution from postnatal day 4 (P4) to P9, and they are evaluated thereafter as follows: Aim 1) At P10 and P35, cerebellar populations are assessed with respect to overall morphology, apoptosis and proliferation. Cortical Purkinje cells and deep interpositus neurons are quantified using unbiased stereology; oligodendrocytes, astrocytes and myelin content are quantified using immunochemistry. Expression and distribution of iron regulatory proteins and of iron-responsive proteins mediating GABA and glutaminergic signaling are measured by western blot and immunohistochemistry. We predict that gestational ID will exacerbate one or more of alcohol's effects on cerebellar populations, and that such changes may persist into adolescence. Aim 2) Cerebellum-dependent learning is tested at P32 using eyeblink classical conditioning (ECC); brains are harvested for the P35 histology / stereology studies of Aim 1. Because the neural circuitry controlling ECC and alcohol's effects upon it are well understood, we can directly correlate the functional and cellular changes. We predict that ID will accentuate the alcohol-induced impairment of ECC, supporting the hypothesis that maternal micronutrient status modulates alcohol's neurotoxicity. Micronutrient supplements offer inexpensive and easy perinatal interventions to reduce alcohol's damage to the fetus. This goal directly fits the NIAAA mission to identify and reduce the causes of alcohol-induced neurodevelopmental and neurobehavioral disorders. PUBLIC HEALTH RELEVANCE: Fetal alcohol syndrome is the leading known cause of mental retardation. This work tests the hypothesis that nutritional factors may exacerbate alcohol's effects upon the fetus or infant. It addresses the concept that nutritional intervention might reduce FASD incidence for women at risk.