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

母亲的铁状况是胎儿酒精综合症的危险因素吗？

• 批准号: 7804567
• 负责人: SUSAN M. SMITH
• 金额: $ 17.83万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7804567
• 关键词: Address; Adolescence; Adult; Affect; African; Alcohol consumption; Alcohol-Induced Disorders; Alcohol-Related Neurodevelopmental Disorder; Alcoholism; Alcohols; Anemia; Apoptosis; Astrocytes; Attenuated; Behavior; Behavioral; Blinking; Brain; Brain region; Cellularity; Cerebellum; Chemistry; Child; Cognitive; Cytoplasmic Granules; Data; Development; Dietary Intervention; Event; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetus; Fibrinogen; Goals; Harvest; Hippocampus (Brain); Histology; Human; Immunochemistry; Immunohistochemistry; Impairment; Incidence; Infant; Inferior; Iron; Iron-Regulatory Proteins; Learning; Life; Malnutrition; Measures; Mediating; Mental Retardation; Mental disorders; Micronutrients; Mission; Modeling; Morphology; Mothers; Motor; Myelin; National Institute on Alcohol Abuse and Alcoholism; Neurons; Nutrient; Nutritional; Oligodendroglia; Olives - dietary; Phosphorus 32; Pilot Projects; Population; Pregnant Women; Prevention; Proteins; Purkinje Cells; Rattus; Risk; Risk Factors; Severities; Signal Transduction; Solutions; Staging; Structure of trigeminal nerve superior sensory nucleus; Suggestion; Testing; Time; Toxic effect; Western Blotting; Woman; Work; alcohol effect; alcohol exposure; classical conditioning; cohort; frontal lobe; gamma-Aminobutyric Acid; insight; interest; micronutrient deficiency; neural circuit; neurobehavioral disorder; neurotoxic; neurotoxicity; offspring; parity; perinatal intervention; postnatal; pregnant; public health relevance; pup

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.

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）是智力迟钝的主要已知原因。其严重程度随着产次的增加而增加，提示产次消耗了一些母体因素，否则会减弱酒精对胎儿的影响。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尚未得到验证。我们假设，奇偶系数/s反映了微量营养素缺乏，经常伴随酗酒。这项R21建议特别关注铁缺乏症（ID），这是孕妇最常见的营养缺乏症。吉西他滨ID导致的行为缺陷与FASD的行为缺陷非常相似，这表明ID和酒精可能协同作用，以提高酒精的神经毒性。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，出生后早期的酒精暴露会破坏小脑神经元群和小脑依赖性学习。具体地，我们将从出生后第4天（P4）至P9将铁充足（IS）或ID妊娠大鼠的后代暴露于酒精或对照溶液中，此后如下评价它们：目的1）在P10和P35，评价小脑群体的总体形态、凋亡和增殖。皮质浦肯野细胞和深间位神经元使用无偏体视学定量;少突胶质细胞、星形胶质细胞和髓鞘含量使用免疫化学定量。通过蛋白质印迹和免疫组织化学测量铁调节蛋白和介导GABA和多巴胺能信号传导的铁响应蛋白的表达和分布。我们预测，妊娠期ID将加剧一个或多个酒精对小脑人口的影响，这种变化可能会持续到青春期。目的2）在P32使用眨眼经典条件反射（ECC）测试小脑依赖性学习;收获脑用于目的1的P35组织学/体视学研究。由于控制ECC的神经回路和酒精对其的影响已经很好地了解，我们可以直接将功能和细胞变化联系起来。我们预测，ID将加重酒精引起的损害ECC，支持这一假设，即母亲的微量营养素状态调节酒精的神经毒性。营养素补充剂提供廉价和容易的围产期干预，以减少酒精对胎儿的损害。这一目标直接符合NIAAA的使命，即确定和减少酒精引起的神经发育和神经行为障碍的原因。 公共卫生相关性：胎儿酒精综合征是导致智力迟钝的主要已知原因。这项工作测试的假设，营养因素可能会加剧酒精对胎儿或婴儿的影响。它涉及的概念，营养干预可能会减少FASD的发病率为妇女的风险。