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

基本信息

批准号：
10669673
负责人：
Deborah A Cory-Slechta
金额：
$ 85.53万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
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

项目摘要

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.

抽象的现在，大量研究报告了空气污染（AP）暴露与神经发育之间的关联疾病（NDD），包括自闭症谱系障碍，精神分裂症和注意力缺陷障碍，所有这些分享许多功能。我对产后早期（人类三个月脑等效）吸入的研究暴露于浓缩环境超级铁（UFP，被认为是AP的最具反应性成分）颗粒（Caps）在小鼠中产生了这些NDD及其其众多神经病理学和行为特征共享假设的机制，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暴露于金属和微量元素的大脑水平明显升高，包括氧化还原金属（Fe，Cu）以及S，CA和Al，指示脑金属异质体的发现。这个建议试图检验总体假设，即AP诱导的脑金属dyshomeostasis有助于男性通过在一系列中测试的神经炎症和氧化应激的产生来偏见的NDD表型旨在加快对机制的理解和这种影响的转化相关性的问题在这些小说，戏剧性和意外发现的5个关键集成问题中：1）有毒痕迹 UFPS的元素污染物是Caps诱导的NDD表型特征的来源，特定升高的大脑 Fe和S（吸入Fe纳米颗粒和/或SO2）都是通过铁毒性和氧化应激机制？ 2）什么是UFP诱导的神经毒性中的男性偏见？它反映了通过活化的小胶质细胞及其与Fe摄取的相互作用，雄性大脑的早期定植？ 3）什么是 UFP进入大脑的门户？我们利用及其扩展的妊娠的非洲早熟小鼠相对于小型C57小鼠的期间，三个月出现了三个月，可以包括鼻腔和嗅觉吸收以确定非洲棘小鼠是否可以作为更相关的人类模型。 4）大脑中的纳米颗粒加工如何影响/调节毒性，并产生有毒的毒性还是保护机制，例如铁蛋白笼的改变？ 5）是人类的验尸后脑组织吗被诊断为NDD（Neurobiobank）的那些含有外源金属纳米颗粒，如我们所见，例如在帽子后，有FE位于callosum callosum的骨髓中受损的髓鞘中？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，以定义最相关的小鼠模型，并确定需要调节空气金属水平以进行公共卫生保护。