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

野火暴露对母亲过敏性哮喘的影响及其对神经生物学的影响

• 批准号: 10727122
• 负责人: Paul Ashwood
• 金额: $ 44.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727122
• 关键词: Acute; Address; Adolescent; Adult; Affect; Air Pollution; Amniotic Fluid; Area; Asthma; Autism Diagnosis; Autopsy; Behavior; Behavior assessment; Behavioral; Brain; Bronchoalveolar Lavage Fluid; California; Cells; Child; Chromatin; Complex; DNA Methylation; Data; Development; Diagnosis; Disease; Droughts; Endothelium; Environment; Environmental Exposure; Environmental Pollutants; Environmental Risk Factor; Epidemiology; Epigenetic Process; Epithelium; Exhibits; Exposure to; Extrinsic asthma; Face; Factor Analysis; Fetal Development; Fetus; Fever; Fire - disasters; Flow Cytometry; Frequencies; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Heritability; Hospitalization; Human; Hypersensitivity; Immune; Immune response; Immune system; Immunologics; Impairment; In Situ; Inflammatory; Inflammatory Response; Intervention; Investigation; Laboratories; Lead; Link; Liquid substance; Maps; Measures; Mediating; Methylation; Microglia; Modeling; Modification; Molecular; Morphology; Mothers; Mus; Neurobiology; Neurodevelopmental Disorder; Neurotransmitters; Observational epidemiology; Particulate Matter; Pathway interactions; Pattern; Pollution; Pre-Clinical Model; Predisposition; Pregnancy; Prevention; Prevention strategy; Process; Production; Public Health; Regulatory Pathway; Reporting; Research; Risk; Sampling; Seasons; Severities; Social Behavior; Social Interaction; Solid; Soot; Source; Standardization; Symptoms; Technology; Testing; Time; Translating; United States; Wildfire; Woman; allergic airway disease; allergic response; asthma exacerbation; asthmatic; autism spectrum disorder; autistic children; behavior test; behavioral impairment; behavioral outcome; behavioral phenotyping; brain tissue; climate change; critical period; cytokine; disorder risk; epigenetic regulation; epigenomics; experimental study; fetal; gene network; glial cell development; immune activation; innovation; interest; maternal immune system; maternal serum; methylome; multiple omics; neurodevelopment; neuroinflammation; neuropathology; novel; offspring; pharmacologic; preclinical study; pregnant; prenatal exposure; prevent; repetitive behavior; response; sex; transcriptome

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.

项目摘要/摘要：自闭症谱系障碍(ASD)是一种非常普遍的终生疾病 没有现成的药物干预手段的疾病。虽然遗传因素很可能 对于这些疾病的贡献者，遗传力估计表明环境有很大的贡献。特别的 有趣的是胎儿怀孕和危重期间母体免疫系统的激活之间的联系 发展阶段。流行病学报告表明，母婴周期之间存在很强的关联 免疫激活和生下患有自闭症儿童的风险增加，包括免疫状况，如 过敏和哮喘。代表哮喘和过敏反应的独特免疫级联反应 在妊娠中期母亲的羊水和母亲血清中检测到，这些母亲的孩子后来被诊断为 ASD.急性加重在怀孕的哮喘妇女中很常见，多达35%的妇女遭受发作 需要住院治疗。此外，空气污染产生的颗粒物是过敏的主要加剧因素 哮喘，已被认为与ASD风险增加有关。野火活动，颗粒物的重要制造者 在规模、严重程度、频率、火季持续时间和易感区域方面，这类物质的数量正在增加。然而， 关于母亲哮喘/过敏介导的反应、野火颗粒的后果，人们知之甚少。 物质(WPM)，或它们对胎儿发育的综合影响。我们已经描述了第一套临床前 对孕期诱发的母亲变态反应性哮喘(MAA)的假设进行检验的研究 在脑神经生物学和后代的功能行为结果方面。我们已经收集了WPM样本 通过野火排放的现场和近距离采样，捕捉现实世界复杂的WPM的复杂性 曝光。我们将测试创新假设，即WPM和MAA结合在一起与严重 对神经发育障碍(NDD)具有高度面部有效性的受损行为终点 和ASD相关症状，这些暴露导致小胶质细胞的表观遗传修饰。这个 拟议的研究将单独检查木质颗粒物以及从北方抽样的木质颗粒物的恶化效果。 加州地区火灾季节和MAA对行为结果的影响(目标1)。怀孕是一段时间 表观遗传变化帮助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，胎儿免疫系统也会被过度激活，损害大脑 发展。我们将检验表观遗传机制控制胎儿小胶质细胞反应的假设。 遵循WPM+MAA(目标2)。如果成功，这项研究将验证NDD对某些人来说是一种 由于常见环境污染物对免疫机制的直接影响而导致的疾病 确定新的机制和预防战略，以解决我们最明显的公共卫生问题之一 时间到了。