The Neuroprotective Effects of Sulforaphane in VPA-Induced Models of Autism

萝卜硫素对 VPA 诱导的自闭症模型的神经保护作用

• 批准号: 10559598
• 负责人: Karen A Litwa
• 金额: $ 18.97万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559598
• 关键词: Acute; Address; Adolescent; Animals; Antioxidants; Behavior; Behavioral; Behavioral Model; Biological Assay; Brain; Broccoli - dietary; Chemical Models; Chemicals; Clinical Trials; Congenital Abnormality; Defense Mechanisms; Development; Developmental Disabilities; Drug Metabolic Detoxication; Embryo; Environment; Environmental Pollutants; Environmental Pollution; Environmental Risk Factor; Exposure to; Fetal Development; Fetus; Genes; Genetic; Homeostasis; Human; Impairment; Incidence; Knockout Mice; Link; Mammals; Mediating; Microelectrodes; Modeling; Monitor; Mus; NF-E2-related factor 2; Neurodevelopmental Disorder; Nitrogen; Organoids; Outcome; Oxidative Stress; Oxygen; Pathway interactions; Pharmacologic Substance; Phenotype; Phytochemical; Pregnant Women; Prevalence; Preventive measure; Production; Research; Risk; Running; Social Interaction; Standardization; Study models; Sulforaphane; Supplementation; Testing; Toxin; Transcriptional Regulation; United States; Up-Regulation; Valproic Acid; Work; autism spectrum disorder; behavioral outcome; combat; confocal imaging; cruciferous vegetable; developmental disease; diagnostic criteria; disability; microphysiology system; mouse model; neural circuit; neural network; neurodevelopment; neuroprotection; oxidative damage; pollutant; prenatal; prenatal exposure; prevent; repetitive behavior; resilience; social communication; synaptogenesis; toxicant; transcription factor

Many environmental pollutants alter physiological homeostasis, and this dysregulation is especially harmful when it occurs embryonically. Unfortunately, pregnant women are commonly exposed to multiple environmental contaminants, which increase the risk of a variety of developmental disorders. For example, several pollutants are known to disrupt neural development. In fact, animal studies show causal links between some pollutants and development of behavior that is typical of autism spectrum disorders (ASD), a group of devastating neurodevelopmental disorders that have become all too common in humans. In fact, neurodevelopmental disorders, such as autism spectrum disorders (ASD), are the fastest growing developmental disabilities in the United States. In 2016 the prevalence of ASD was nearly 2% and its incidence has doubled in the last 20 years. Indeed, it is widely recognized that genetic and environmental factors, such as exposure to pollutants, interact to increase the risk of developing an ASD. While we have evolved defense mechanisms to mitigate the effects of natural toxins, they are insufficient to combat today’s ever-increasing environmental contamination. However, if we can augment our endogenous preventative mechanisms, we can prevent pollutant-induced disabilities. We recently determined in the mouse model that pollutant-exposed fetuses supplemented with sulforaphane, a derivative of broccoli, have less frequent and less severe birth defects relative to embryos exposed to only pollutants. This project will test the generality of that rescue effect by determining the mechanisms through which we can prevent chemical-induced alterations in neural circuitry and associated behaviors. Fetal exposure to valproic acid (VPA) is known to cause ASD in humans and autism-like behavior in mice. Here we will exploit this model to understand the mechanisms of resilience that sulforaphane upregulates to protect the fetus from developing autism. Specifically, using human brain organoids we will establish the mechanisms by which it reduces VPA-mediated alterations in neural circuit development. We will then assess the impact of sulforaphane on VPA-induced behavioral outcomes in the VPA mouse model. This research benefits from the combined strengths of a robust model of chemical-induced ASD, a human brain microphysiological system, and a mouse behavioral model. This unprecedented approach will allow us to identify preventative measures that facilitate normal neural circuit development in a toxic environment.

许多环境污染物改变了身体稳态，这种失调尤其有害 当它发生胚胎时。不幸的是，孕妇通常暴露于多种环境 污染物增加了各种发育障碍的风险。例如，几种污染物 已知会破坏神经发育。实际上，动物研究表明某些污染物与 自闭症谱系疾病（ASD）的典型行为的发展，一群毁灭性的行为 在人类中变得太普遍的神经发育障碍。实际上，神经发育 自闭症谱系障碍（ASD）等疾病是增长最快的发育障碍 美国。在2016年，ASD的患病率几乎为2％，在过去20年中，其事件已翻了一番。 确实，人们普遍认为，遗传和环境因素（例如暴露于污染物）相互作用 增加开发ASD的风险。虽然我们发展了防御机制来减轻效果 在天然毒素中，它们不足以应对当今日益增加的环境污染。然而， 如果我们可以增加内源性预防机制，我们可以防止污染物引起的残疾。我们 最近在小鼠模型中确定的是污染物暴露的胎儿 西兰花的衍生物，相对于仅暴露于 污染物。该项目将通过确定通过的机制来测试该救援效应的普遍性 我们可以防止化学诱导的神经回路和相关行为的改变。胎儿暴露 已知丙戊酸（VPA）在人类中引起ASD，而小鼠的自闭症行为。在这里，我们将利用这个 了解磺胺素更新以保护胎儿免受的弹性机制的模型 发展自闭症。具体而言，使用人脑器官，我们将建立它的机制 减少了VPA介导的神经回路发展的改变。然后，我们将评估磺胺的影响 在VPA小鼠模型中通过VPA诱导的行为结果。这项研究受益于联合的 化学诱导的ASD，人脑微生物生理系统和小鼠的强大模型的强度 行为模型。这种前所未有的方法将使我们能够确定促进的预防措施 在有毒环境中的正常神经回路发展。