The effects of wildfire exposure on maternal allergic asthma and consequences on neurobiology

项目摘要/摘要：自闭症谱系障碍（ASD）是普遍的，高度流行的终身 药物干预不容易获得的疾病。虽然遗传因素很可能 对于这些疾病的贡献者，遗传性估计表明环境的贡献很大。特别 感兴趣的是胎儿妊娠和母亲免疫系统的激活之间的联系， 发展时期。流行病学报告表明，产妇分娩的时间与产妇死亡的时间有很强的相关性。 免疫激活和患ASD儿童的风险增加，包括免疫状况， 过敏和哮喘独特的免疫级联反应代表哮喘和过敏反应， 检测羊水和母亲的血清中怀孕中期的孩子后来被诊断为 自闭症急性加重在怀孕的哮喘妇女中很常见，多达35 需要住院治疗。此外，来自空气污染的颗粒物是过敏性疾病的主要加重因素， 哮喘与ASD风险增加有关。野火活动，一个重要的生产商的颗粒 随着火灾的发生，火灾的规模、严重程度、频率、火灾季节的持续时间和易受影响的地区都在增加。然而，在这方面， 对母体哮喘/过敏介导的反应的后果知之甚少，野火颗粒 物质（WPM），或其对胎儿发育的综合影响。我们已经描述了第一组临床前 研究旨在检验妊娠期间诱发的母体过敏性哮喘（MAA）会改变 大脑神经生物学和后代的功能行为结果。我们在下列地点收集了“运动”样本： 现场和通过野火排放的近距离采样，捕捉现实世界复杂的WPM的复杂性 暴露。我们将测试创新的假设，即WPM和MAA相结合，是因果关系严重 对神经发育障碍（NDD）具有高度表面效度的受损行为终点 和ASD相关症状，并且这些暴露导致小胶质细胞的表观遗传修饰。的 拟议的研究将审查单独的WPM和WPM的加剧影响，从北方取样 加州地区在火灾季节和MAA的行为结果（目标#1）。怀孕期间 表观遗传变化有助于静态基因组适应母体环境，因此，如果母体免疫 系统被过度激活，胎儿的免疫系统也将被过度激活，以牺牲大脑 发展我们将测试这一假设，即表观遗传机制控制小胶质细胞的反应，在胎儿 遵循WPM + MAA（目标#2）。如果成功的话，这项研究将验证NDD对某些人来说是一种 由于常见的环境污染物对免疫机制的直接影响而引起的疾病， 确定新的机制和预防战略，为我们最明显的公共卫生问题之一， 时间

Project Summary/Abstract: Autism spectrum disorders (ASD) are pervasive, highly prevalent lifelong disorders for which pharmacological interventions are not readily available. While genetic factors are likely contributors to these disorders, heritability estimates indicate strong environmental contributions. Of particular interest is the link between fetal gestation and the activation of the maternal immune system during critical periods of development. Epidemiological reports suggest a strong association between periods of maternal immune activation and an increased risk of having a child with ASD including immune conditions such as allergies and asthma. Unique immune cascades representative of asthma and allergy responses have been detected in amniotic fluid and maternal serum mid pregnancy of mothers whose child was later diagnosed with ASD. Acute exacerbations are common in pregnant asthmatic women with as many 35% suffering attacks requiring hospitalization. In addition, particulate matter from air pollution, a major exacerbating factor in allergic asthma, has been linked with an increased risk for ASD. Wildfire activity, a significant producer of particulate matter, is increasing in size, severity, frequency, duration of fire season and areas of susceptibility. However, little is known about the consequences of maternal asthma/allergy mediated responses, wildfire particulate matter (WPM), or their combined effects on fetal development. We have described the first set of preclinical studies to test the hypothesis that maternal allergic asthma (MAA) induced during gestation imparts alterations in brain neurobiology and functional behavioral outcomes in the offspring. We have WPM samples collected in situ and through proximity sampling of wildfire emissions, capturing the complexity of real-world complex WPM exposures. We will test the innovative hypothesis that WPM and MAA combined are causally linked to severe impaired behavioral endpoints that have a high degree of face validity for neurodevelopmental disorders (NDD) and ASD-relevant symptoms, and that these exposures lead to epigenetic modifications of microglia. The proposed studies will examine WPM alone and the exacerbating effects of WPM sampled from Northern California region during fire season and MAA on behavioral outcomes (Aim #1). Pregnancy is a time when epigenetic changes help a static genome adapt to the maternal environment, so that if the maternal immune system is overly activated, the fetal immune system will also be over activated at the expense of brain development. We will test the hypothesis that epigenetic mechanisms control microglia responses in the fetus following WPM + MAA (Aim #2). If successful, this research will validate the concept that NDD is, for some, a disorder due to the direct effects of common environmental contaminants on immune mechanisms that will identify novel mechanisms and preventative strategies for one of the most visible public health concerns of our time.