Gene-environment interactions in the developmental neurotoxicity of air pollution

来自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 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贡献者，而柴油尾气(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，围产期暴露可能导致或促成发育障碍和行为异常。特别是，最近的一些研究发现，暴露于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，自闭症谱系障碍的特征是社交和沟通障碍，以及重复和不寻常行为的存在。ASD的病因(S)尚不清楚，虽然它可能有遗传成分，但环境因素越来越被怀疑在其病因中发挥关键作用，特别是在遗传易感个体中。自闭症儿童表现出更高水平的神经炎症和全身炎症，这也是暴露在与交通相关的空气污染中的特征。在一系列的初步研究中，我们发现，围产期暴露于DE的小鼠(从孕期第0天到出生后第21天)在与ASD相关的领域(沟通、社交、重复行为)引起了许多行为变化。本建议的目的是调查发育中DE暴露引起的生化、分子和形态变化，这些变化可能与ASD有关。特别是，我们将测试这一假设，即DE诱导的神经炎症将改变信号级联，通过表观遗传学变化导致reelin表达减少，这反过来将影响皮质形态发生并导致皮质分层中断，如ASD所见。我们还将通过评估DE暴露对reelin杂合小鼠(rl+/%)和Gclm+/%小鼠的发育神经毒性来研究基因与环境的相互作用。Rl+/%小鼠将允许直接测试“卷轴假说”，预计将更容易受到DE的影响。Gclm+/%小鼠是一种非常常见的遗传多态的模型，我们已经证明它们更容易受到急性DE神经毒性的影响。总之，这些研究将为DE作为与交通相关的空气污染的指标，导致可能与ASD相关的行为、生化和形态改变的能力提供证据，并将提供新的基因-环境相互作用的证据。

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.