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

许多环境污染物改变了生理稳态，这种失调尤其有害 当它发生在胚胎时。不幸的是，孕妇通常暴露于多种环境中， 污染物，这增加了各种发育障碍的风险。例如，几种污染物 会扰乱神经发育事实上，动物研究表明，一些污染物和 自闭症谱系障碍（ASD）的典型行为发展，一组毁灭性的 神经发育障碍已经在人类中变得非常普遍。事实上， 自闭症谱系障碍（ASD）是世界上增长最快的发育障碍， 美国的2016年，ASD的患病率接近2%，其发病率在过去20年中翻了一番。 事实上，人们普遍认识到，遗传和环境因素，如接触污染物， 会增加患自闭症的风险虽然我们进化出了防御机制来减轻 尽管这些方法对天然毒素的使用量很大，但它们不足以对抗当今日益严重的环境污染。然而，在这方面， 如果我们能够加强我们的内在预防机制，我们就能够防止污染引起的残疾。我们 最近在小鼠模型中确定，暴露于污染物的胎儿补充萝卜硫素， 西兰花的衍生物，相对于只暴露于西兰花的胚胎， 污染物这个项目将通过确定通过何种机制来测试这种救援效果的普遍性， 我们可以防止化学物质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）引起人类的ASD和小鼠的自闭症样行为。在这里，我们将利用这一点 模型来了解萝卜硫素上调以保护胎儿免受 发展成自闭症具体来说，使用人脑类器官，我们将建立它的机制， 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。这项研究得益于 化学诱导的ASD、人脑微生理系统和小鼠的稳健模型的优势 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， 神经回路在有毒环境中的正常发育

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.