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

许多环境污染物会改变生理动态平衡，这种失调尤其有害 当它发生在胚胎上的时候。不幸的是，孕妇通常暴露在多种环境中。 污染物，这会增加患各种发育障碍的风险。例如，几种污染物 都会扰乱神经发育。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 神经发育障碍在人类中已经变得太常见了。事实上，神经发育 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，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，相互作用。 增加患自闭症的风险。虽然我们已经进化出防御机制来减轻 在天然毒素中，它们不足以对抗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，我们就可以防止污染物导致的残疾。我们 最近在小鼠模型中确定，接触污染物的胎儿补充萝卜硫素，一种 与仅接触西兰花的胚胎相比，西兰花的衍生品具有较少的频率和较轻的出生缺陷 污染物。该项目将通过确定以下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)会导致人类的ASD和小鼠的自闭症样行为。在这里，我们将利用这一点 用模型来理解萝卜硫素上调以保护胎儿的弹性机制 发展成自闭症。具体地说，使用人脑有机化合物，我们将建立它的机制 减少VPA介导的神经回路发育的改变。然后我们将评估萝卜硫素的影响 关于VPA诱导的VPA小鼠模型的行为结果。这项研究得益于 化学诱导ASD的健壮模型、人脑微生理系统和小鼠的优点 行为模型。这一史无前例的方法将使我们能够确定预防措施，促进 在有毒环境中正常的神经回路发育。

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.