权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要现在许多研究报告空气污染(AP)暴露与神经发育之间的关系精神障碍(NDDS)，包括自闭症谱系障碍、精神分裂症和注意力缺陷障碍，所有这些共享众多功能。我对出生后早期(相当于人的晚期妊娠脑)吸入的研究暴露于浓缩的环境超细颗粒物(UFP，被认为是AP最活跃的成分) (CAPS)在小鼠体内产生了这些NDD及其各自的神经病理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学习。此外，CAPS暴露会显著提高大脑中的金属和微量元素水平，包括氧化还原金属(铁、铜)以及S、钙和铝，这些发现表明大脑金属代谢紊乱。这项建议旨在验证AP诱导的脑金属代谢紊乱有助于男性-- 通过神经炎症和氧化应激的产生而产生的偏向NDD表型在一系列旨在加速理解这些影响的机制和翻译相关性的问题在这些新奇、戏剧性和意想不到的发现产生的5个关键综合问题中：1)是有毒的痕迹 UFP的元素污染是CAPS诱导的NDD表型特征的来源，特别是大脑升高铁和S(吸入纳米铁和/或二氧化硫)，这两种药物都是已知的神经毒物，通过铁中毒和氧化应激机制？2)在UFP诱导的神经毒性中，男性偏向的原因是什么？它是否反映了一个激活的小胶质细胞对男性大脑的早期定植及其与铁摄取的相互作用？3)什么是 UFP进入大脑的入口是什么？我们利用早熟的非洲多刺小鼠延长妊娠相对于正常C57小鼠的时期，在出生后的第三个月，可包括鼻腔和嗅觉吸收以确定非洲多刺小鼠是否可能作为更相关的人类模型。4) 纳米颗粒在大脑中的处理如何随后影响/调节毒性，以及它是否产生毒性或者保护机制，比如铁蛋白笼中的变化？5)人类死后的脑组织如我们所见，被诊断为NDDS(神经生物库)的含有外源金属纳米颗粒，例如，在CAP后，Fe是否位于损伤的骨痂髓鞘内？这些综合努力将开始阐述AP诱导的NDDS的机制和相关的性别差异，以定义最相关的小鼠模型，并确定是否有必要管制空气中的金属水平，以保护公众健康。