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.

许多环境污染物会改变生理稳态，这种失调尤其有害 当它发生在胚胎时期时。不幸的是，孕妇通常会暴露在多种环境中 污染物，会增加各种发育障碍的风险。例如，多种污染物 已知会破坏神经发育。事实上，动物研究表明一些污染物和污染物之间存在因果关系。 典型的自闭症谱系障碍 (ASD) 行为的发展，这是一组具有破坏性的疾病 神经发育障碍在人类中已经变得非常普遍。事实上，神经发育 诸如自闭症谱系障碍 (ASD) 等疾病是世界上增长最快的发育障碍 美国。 2016 年，自闭症谱系障碍 (ASD) 的患病率接近 2%，且在过去 20 年中其发病率翻了一番。 事实上，人们普遍认识到遗传因素和环境因素（例如接触污染物）会相互作用。 增加患 ASD 的风险。虽然我们已经进化出防御机制来减轻影响 尽管含有大量天然毒素，但它们不足以应对当今日益严重的环境污染。然而， 如果我们能够加强我们的内源性预防机制，我们就能够预防污染物引起的残疾。我们 最近在小鼠模型中确定，暴露于污染物的胎儿补充了萝卜硫素（一种 西兰花的衍生物，与仅暴露于西兰花的胚胎相比，出生缺陷的频率和严重程度较低 污染物。该项目将通过确定救援效果的机制来测试救援效果的普遍性。 我们可以防止化学引起的神经回路和相关行为的改变。胎儿暴露于 已知丙戊酸（VPA）会导致人类自闭症谱系障碍（ASD）和小鼠自闭症样行为。在这里我们将利用这个 模型来了解萝卜硫素上调以保护胎儿的恢复机制 发展为自闭症。具体来说，我们将利用人脑类器官建立其机制 减少 VPA 介导的神经回路发育改变。然后我们将评估萝卜硫素的影响 VPA 小鼠模型中 VPA 诱导的行为结果。这项研究受益于综合 化学诱导自闭症谱系障碍的稳健模型、人脑微生理系统和小鼠的优势 行为模型。这种前所未有的方法将使我们能够确定预防措施，以促进 有毒环境中神经回路的正常发育。