课题基金 / 基金详情

项目摘要

项目成果

Deborah A Cory-Slechta的其他基金

相似基金

相关文献

中文摘要
翻译
摘要
英文摘要
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.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1038/s41583-022-00672-8
发表时间: 2023-03
期刊: Nature reviews. Neuroscience
影响因子: --
作者: []
通讯作者:
Early Life Air Pollution Exposures as a Risk Factor for Neurodevelopmental Disorders
  • 批准号:
    10197383
  • 项目类别:
  • 资助金额:
    $89.05万
  • 财政年份:
    2021
  • 负责人:
    Deborah A Cory-Slechta
  • 依托单位:
Early Life Air Pollution Exposures as a Risk Factor for Neurodevelopmental Disorders
  • 批准号:
    10459253
  • 项目类别:
  • 资助金额:
    $86.6万
  • 财政年份:
    2021
  • 负责人:
    Deborah A Cory-Slechta
  • 依托单位:
Air Pollution, Elevated Brain Iron and Alzheimer's Disease
  • 批准号:
    10285494
  • 项目类别:
  • 资助金额:
    $38.08万
  • 财政年份:
    2020
  • 负责人:
    Deborah A Cory-Slechta
  • 依托单位:
Animal Behavior & Neurophysiology
  • 批准号:
    10633160
  • 项目类别:
  • 资助金额:
    $18.45万
  • 财政年份:
    2020
  • 负责人:
    Deborah A Cory-Slechta
  • 依托单位:
海外基金