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:
    10459253
  • 负责人:
  • 金额:
    $ 86.6万
  • 依托单位:
  • 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

项目成果

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Deborah A Cory-Slechta其他文献

Deborah A Cory-Slechta的其他文献

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{{ truncateString('Deborah A Cory-Slechta', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 86.6万
  • 项目类别:
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:
    10669673
  • 财政年份:
    2021
  • 资助金额:
    $ 86.6万
  • 项目类别:
Air Pollution, Elevated Brain Iron and Alzheimer's Disease
空气污染、脑铁含量升高和阿尔茨海默病
  • 批准号:
    10285494
  • 财政年份:
    2020
  • 资助金额:
    $ 86.6万
  • 项目类别:
Animal Behavior & Neurophysiology
动物行为
  • 批准号:
    10633160
  • 财政年份:
    2020
  • 资助金额:
    $ 86.6万
  • 项目类别:
Animal Behavior & Neurophysiology
动物行为
  • 批准号:
    10226349
  • 财政年份:
    2020
  • 资助金额:
    $ 86.6万
  • 项目类别:
Animal Behavior & Neurophysiology
动物行为
  • 批准号:
    10445286
  • 财政年份:
    2020
  • 资助金额:
    $ 86.6万
  • 项目类别:
Air Pollution and Male-Biased Psychiatric Disorders
空气污染和男性偏向的精神疾病
  • 批准号:
    10436343
  • 财政年份:
    2020
  • 资助金额:
    $ 86.6万
  • 项目类别:
Air Pollution and Male-Biased Psychiatric Disorders
空气污染和男性偏向的精神疾病
  • 批准号:
    10265538
  • 财政年份:
    2020
  • 资助金额:
    $ 86.6万
  • 项目类别:
Air Pollution and Male-Biased Psychiatric Disorders
空气污染和男性偏向的精神疾病
  • 批准号:
    10065880
  • 财政年份:
    2020
  • 资助金额:
    $ 86.6万
  • 项目类别:
Animal Behavior & Neurophysiology
动物行为
  • 批准号:
    10085504
  • 财政年份:
    2020
  • 资助金额:
    $ 86.6万
  • 项目类别:

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