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: 10459253
• 负责人: Deborah A Cory-Slechta
• 金额: $ 86.6万
• 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/10459253
• 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.

摘要 许多研究现在报告了空气污染（AP）暴露与神经发育之间的联系。 精神分裂症和注意力缺陷障碍，所有这些疾病都 有许多共同的特点。我对出生后早期（人类第三孕期脑当量）吸入的研究 暴露于浓缩的环境超细（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 共享的假设机制，包括男性偏见，为流行病学提供生物学上的可解释性， 问题研究此外，CAPS暴露显着提高了金属和微量元素的大脑水平，包括 氧化还原金属（Fe、Cu）以及S、Ca和Al，结果表明脑金属稳态异常。这项建议 旨在测试总体假设，即AP诱导的脑金属代谢障碍有助于男性- 通过一系列的神经炎症和氧化应激测试， 旨在加速理解机制的问题，以及这些效应的翻译相关性 在5个关键的综合问题，从这些新的，戏剧性的和意想不到的发现：1）是有毒的痕迹 UFPs的元素污染物是CAPS诱导的NDD表型特征的来源，特别是脑组织中 Fe和S（吸入的Fe纳米颗粒和/或SO2），两者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，男性偏好的原因是什么？它是否反映了一个 激活的小胶质细胞在男性大脑中的早期定植及其与铁摄取的相互作用？3)有哪些 UFP进入大脑的入口？我们利用早熟的非洲多刺小鼠， 相对于晚期C57小鼠，晚期妊娠发生在出生后，可包括鼻和 嗅觉吸收，以确定是否非洲多刺小鼠可能作为一个更相关的人类模型。四、 脑中的纳米颗粒处理如何随后影响/调节毒性，以及它是否产生毒性 或保护机制例如，铁蛋白笼的改变5)人类死后的脑组织 已经被诊断患有NDD（神经生物库）的患者，如我们所见， CAPS后胼胝体中受损髓鞘内的Fe？这些综合努力将开始， 详细阐述AP诱导的NDD和相关性别差异的机制，以确定最相关的小鼠 模型，并确定是否需要管制空气中的金属水平，以保护公众健康。