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生理稳态，这种失调是特别有害的