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：
9752531
负责人：
LUCIO G COSTA
金额：
$ 33.85万
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/9752531
关键词：
Acute Address Affect Age Air Pollutants Air Pollution Animal Model Animals Area 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 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 perinatal period 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.

越来越多的人类流行病学和动物研究证据表明空气可能污染对中枢神经系统 (CNS) 产生负面影响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原因，而柴油机尾气 (DE) 是其最重要的组成部分。一些研究表明，年轻人可能尤其如此。容易受到空气污染引起的神经毒性的影响，并且围产期接触可能导致或导致发育障碍和行为异常。特别是，最近的一些研究发现，接触与交通相关的空气污染与自闭症谱系障碍（ASD）之间存在关联，其特点是社交能力受损和自闭症谱系障碍的病因尚不清楚，虽然它可能具有遗传成分，但越来越多的人怀疑环境因素在其病因学中发挥着关键作用，特别是在遗传易感人群中。自闭症儿童表现出较高水平的神经炎症和全身炎症，这也是暴露于交通相关空气污染的标志。在一系列初步研究中，我们发现小鼠在围产期暴露于 DE（从妊娠第 0 天到第 0 天）。出生后第 21 天）引起了与 ASD 相关的领域（沟通、社交、重复行为）的许多行为改变。本提案的目的是调查可能相关的发育性 DE 暴露引起的生化、分子和形态学改变。特别是对于自闭症谱系障碍（ASD），我们将测试这样的假设：DE 诱导的神经炎症将改变信号级联，通过表观遗传变化导致 reelin 表达减少，这反过来又会影响皮质形态发生并导致。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-环境相互作用。直接测试“reelin假说”并预计更容易受到DE的影响 Gclm+/%小鼠是非常常见的遗传多态性的模型，我们已经证明它们更容易受到DE的影响。总而言之，这些研究将提供证据证明 DE 作为交通相关空气污染的指标，引起可能与 ASD 相关的行为、生化和形态改变，并将提供新基因的证据。 -环境相互作用。