Gene-environment interactions in the developmental neurotoxicity of air pollution

空气污染发育神经毒性中的基因-环境相互作用

基本信息

批准号：
9358989
负责人：
LUCIO G COSTA
金额：
$ 33.91万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9358989
关键词：
Acute Address Affect Age Air Pollutants Air Pollution Animal Model Animals Area Autistic Disorder Behavior Behavioral Biochemical Brain Cardiovascular Diseases Central Nervous System Diseases Communication Development Developmental Disabilities Diesel Exhaust Disease Environmental Risk Factor Epidemiology Epigenetic Process Etiology Event Exposure to GCLM gene Genetic Polymorphism Genetic Predisposition to Disease Goals Homeostasis Human Impairment Incidence Individual Inflammation Inherited Lung diseases Modeling Molecular Morbidity - disease rate Morphogenesis Morphology Mus Mutation Neuraxis Neurodevelopmental Disorder Oxidative Stress Particulate Matter Perinatal Perinatal Exposure Phenotype Play Predisposition Pregnancy Prevalence Role Series Signal Transduction Socialization Testing Transgenic Mice Weaning Wild Type Mouse autism spectrum disorder autistic children base developmental neurotoxicity gene environment interaction in utero male mortality mouse model negative affect neuroinflammation neurotoxicity novel postnatal repetitive behavior traffic-related air pollution ultrafine particle

项目摘要

Increasing evidence from human epidemiological and animal studies suggests that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity, and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which is characterized by impairment in socialization and in communication, and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals. Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. In a series of preliminary studies we have found that perinatal exposure of mice to DE (from gestational day 0 to postnatal day 21) caused a number of behavioral alterations in the domains relevant to ASD (communication, sociability, repetitive behaviors). The aim of the present proposal is to investigate biochemical, molecular, and morphological alterations caused by developmental DE exposure that may be relevant for ASD. In particular, we will test the hypothesis that DE-induced neuroinflammation will alter a signaling cascade leading, through epigenetic changes, to a decreased expression of reelin, and this in turn will affect cortical morphogenesis and cause disruption of cortical layering, as seen in ASD. We will also investigate gene-environment interactions by assessing the developmental neurotoxicity of DE exposure in reelin heterozygous mice (rl+/%) and in Gclm+/% mice. The rl+/% mice will allow a direct testing of the “reelin hypothesis” and are expected to be more susceptible to the effects of DE. The Gclm+/% mice are a model for a very common genetic polymorphism, and we have shown that they are more susceptible to acute DE neurotoxicity. Altogether, these studies will provide evidence on the ability of DE, as an indicator of traffic-related air pollution, to cause behavioral, biochemical and morphological alterations which may be relevant to ASD, and will provide evidence of novel gene-environment interactions.

人类流行病学和动物研究的越来越多的证据表明，空气污染可能负面影响中枢神经系统（CNS），并导致中枢神经系统疾病。与交通相关的空气污染是全球空气污染的主要因素，柴油排气（DE）是其最重要的组成部分。几项研究表明，年轻人可能特别容易受到空气污染引起的神经毒性的影响，并且围产期暴露可能导致或导致发育障碍和行为异常。特别是，许多最近的研究发现，与交通相关的空气污染与自闭症谱系障碍（ASD）之间的暴露之间存在关联，这些疾病的特征是社会化和交流中的障碍，以及存在重复性和异常行为。 ASD的原因是未知的，尽管它可能具有遗传成分，但越来越多地怀疑环境因素在其病因中起着关键作用，尤其是在一般易感的个体中。自闭症儿童表现出更高水平的神经炎症和全身感染，这也是暴露于交通相关的空气污染的标志。在一系列初步研究中，我们发现小鼠围产期暴露于DE（从妊娠第0天到产后第21天）导致与ASD相关的域（交流，社交，重复行为）的域中发生了许多行为改变。本提案的目的是研究可能与ASD相关的发育暴露引起的生化，分子和形态变化。特别是，我们将检验以下假设：去诱导的神经炎症将通过表观遗传学变化改变引起的信号级联反应，以减少reelin的表达，这反过来又会影响皮质形态发生并导致皮质分层的破坏，如ASD所示。我们还将通过评估Reelin杂合小鼠（RL+/％）和GCLM+/％小鼠中DE暴露的发育神经毒性来研究基因环境的相互作用。 RL+/％小鼠将直接测试“ reelin假设”，并有望更容易受到DE的影响。 GCLM+/％小鼠是一种非常常见的遗传多态性的模型，我们已经表明它们更容易受到急性DE神经毒性的影响。总的来说，这些研究将提供有关DE作为交通相关空气污染的能力的证据，导致可能与ASD相关的行为，生化和形态学改变，并将提供新型基因环境相互作用的证据。