Early Life Air Pollution Exposures as a Risk Factor for Neurodevelopmental Disorders

生命早期接触空气污染是神经发育障碍的危险因素

• 批准号: 10197383
• 负责人: Deborah A Cory-Slechta
• 金额: $ 89.05万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2029-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10197383
• 关键词: African; Air; Air Pollution; Attention Deficit Disorder; Autopsy; Behavioral; Biological; Brain; Corpus Callosum; Diagnosis; Exposure to; Ferritin; Health protection; Individual; Inhalation; Inhalation Exposure; Life; Metals; Microglia; Mus; Myelin; Neurodevelopmental Disorder; Neurotoxins; Nose; Oxidation-Reduction; Oxidative Stress; Phenotype; Pregnancy; Process; Production; Public Health; Reporting; Risk Factors; Schizophrenia; Series; Sex Differences; Source; Stress Tests; Testing; Third Pregnancy Trimester; Toxic effect; Trace Elements; Ultrafine; autism spectrum disorder; brain tissue; design; epidemiology study; human model; human tissue; male; mouse model; nanoparticle; neuroinflammation; neurotoxicity; novel; particle; particle exposure; postnatal; postnatal human; uptake

ABSTRACT Numerous studies now report associations between air pollution (AP) exposure and neurodevelopmental disorders (NDDs), including autism spectrum disorder, schizophrenia, and attention deficit disorder, all of which share numerous features. My studies of early postnatal (human 3rd trimester brain equivalent) inhalation exposures to concentrated ambient ultrafine (UFP, considered the most reactive component of AP) particles (CAPS) in mice produced numerous neuropathological and behavioral features of these NDDs and of their shared hypothesized mechanisms, including male bias, providing biological plausibility for the epidemiological studies. Additionally, CAPS exposures markedly elevated brain levels of metals and trace elements, including redox metals (Fe, Cu) as well as S, Ca, and Al, findings indicative of brain metal dyshomeostasis. This proposal seeks to test the overarching hypothesis that AP-induced brain metal dyshomeostasis contributes to male- biased NDD phenotypes via production of neuroinflammation and oxidative stress tested in a series of questions designed to accelerate the understanding of mechanisms, and translational relevance of such effects in 5 key integrated questions emanating from these novel, dramatic and unexpected findings: 1) Are toxic trace element contaminants of UFPs a source of CAPS-induced NDD phenotypic features, specifically elevated brain Fe and S (inhaled Fe nanoparticles and/or SO2) both of which are known neurotoxicants via ferroptotic and oxidative stress mechanisms? 2) What accounts for male bias in UFP-induced neurotoxicity? Does it reflect an earlier colonization of male brain by activated microglia and their interactions with Fe uptake? 3) What are the portals of entry of UFPs into brain? We utilize the precocial African spiny mouse with its extended gestational period relative to the altricial C57 mouse in which 3rd trimester occurs postnatally and can include nasal and olfactory uptake to determine whether the African spiny mouse might serve as a more relevant human model. 4) How does nanoparticle processing in brain subsequently influence/modulate toxicity and does it generate toxic or protective mechanisms e.g., alterations in the ferritin cage? 5) Does post-mortem brain tissue from humans that had been diagnosed with NDDs (Neurobiobank) contain exogenous metal nanoparticles as we see, e.g., with Fe located within damaged myelin in corpus callosum after CAPS? These integrated efforts will begin to elaborate mechanisms of AP-induced NDDs and associated sex differences, to define the most relevant mouse model, and to determine the need to regulate air metal levels for public health protection.

抽象的 目前，大量研究报告了空气污染 (AP) 暴露与神经发育之间的关联 障碍 (NDD)，包括自闭症谱系障碍、精神分裂症和注意力缺陷障碍，所有这些 共享许多功能。我对产后早期（人类妊娠第三个月大脑等效）吸入的研究 暴露于浓缩环境超细颗粒（UFP，被认为是 AP 中最具反应性的成分）颗粒 (CAPS) 在小鼠中产生了这些 NDD 及其相关的许多神经病理学和行为特征 共同的假设机制，包括男性偏见，为流行病学提供了生物学上的合理性 研究。此外，CAPS 暴露显着提高了大脑中金属和微量元素的水平，包括 氧化还原金属（Fe、Cu）以及 S、Ca 和 Al，这些结果表明脑金属动态平衡失调。这个提议 旨在检验 AP 诱导的脑金属失衡会导致男性的总体假设 通过在一系列测试中测试的神经炎症和氧化应激的产生而导致 NDD 表型偏向 旨在加速理解机制以及此类效应的转化相关性的问题 这些新颖、戏剧性和意想不到的发现产生了 5 个关键的综合问题：1) 是否含有微量有毒物质 UFP 的元素污染物是 CAPS 诱导的 NDD 表型特征的来源，特别是脑部升高 Fe 和 S（吸入的 Fe 纳米颗粒和/或 SO2）都是已知的神经毒剂，可通过铁死亡和 氧化应激机制？ 2) 是什么原因导致UFP引起的神经毒性中男性偏向？它是否反映了 激活的小胶质细胞在男性大脑中的早期定植及其与铁吸收的相互作用？ 3）有哪些 UFP 进入大脑的门户？我们利用早熟的非洲刺鼠及其延长的妊娠期 相对于晚熟 C57 小鼠的时期，其中第三个三个月发生在出生后，可以包括鼻和 嗅觉吸收以确定非洲刺鼠是否可以作为更相关的人类模型。 4） 大脑中的纳米颗粒处理随后如何影响/调节毒性以及它是否产生有毒物质 或保护机制，例如铁蛋白笼的改变？ 5）死后脑组织是否来自人类 正如我们所见，被诊断为 NDD（Neurobiobank）的细胞含有外源性金属纳米颗粒，例如， CAPS 后 Fe 位于胼胝体受损髓鞘内？这些综合努力将开始 AP 诱导的 NDD 和相关性别差异的详细机制，以确定最相关的小鼠 模型，并确定为了保护公众健康而调节空气金属水平的需要。