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; 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）是智力低下的主要原因。它的严重程度随着平价的增加而增加，促使人们的建议耗尽了某些母体因素，这些因素否则会减弱酒精对胎儿的影响。尽管许多人推测该因素是营养的，但该假设在很大程度上未经测试。我们假设奇偶元因素反映了经常伴随酒精中毒的微量营养素缺陷。该R21提案专门针对铁缺乏症（ID），这是孕妇最常见的营养缺乏。妊娠ID会导致行为缺陷，这与FASD较密切相似，这表明ID和酒精可能协同增强酒精的神经毒性。这项试验研究收集了支持该假设的初步数据。我们将使用已建立的大鼠模型检验这一假设，在该模型中，早期产后酒精暴露会破坏小脑神经元种群和小脑依赖性学习。具体而言，我们将暴露于从产后第4天（P4）到P9的饮酒或对照溶液的铁含量（IS）或ID怀孕大鼠的后代，此后在P10和P35上对它们进行评估，如下所示，在P10和P35上，小脑种群对整体形态学，凋亡和凋亡进行评估。皮质的浦肯野细胞和深层神经元使用无偏的立体学定量。使用免疫化学对少突胶质细胞，星形胶质细胞和髓磷脂含量进行定量。铁调节蛋白以及介导GABA和谷氨酰胺能信号传导的铁响应蛋白的表达和分布均通过蛋白质印迹和免疫组织化学测量。我们预测，妊娠ID会加剧酒精对小脑种群的一种或多种影响，并且这种变化可能会持续到青春期。目标2）使用EykeBlink经典条件（ECC）在p32上测试小脑依赖性学习；为AIM 1的p35组织学 /立体学研究收集大脑。由于控制ECC和酒精对其作用的神经回路已充分了解，因此我们可以直接将功能和细胞变化关联。我们预测，ID将突出酒精引起的ECC损伤，支持孕产妇微量营养素状态调节酒精的神经毒性的假设。微量营养素补充剂提供廉价且易于围产期干预措施，以减少酒精对胎儿的损害。该目标直接符合NIAAA的使命，以识别和减少酒精引起的神经发育和神经行为疾病的原因。 公共卫生相关性：胎儿酒精综合症是智力降低的主要原因。这项工作检验了以下假设：营养因素可能加剧酒精对胎儿或婴儿的影响。它解决了这样一个概念，即营养干预可能会减少有风险妇女的FASD发病率。