Gene-environment interactions in the developmental neurotoxicity of air pollution

越来越多的人类流行病学和动物研究证据表明，空气污染可能 对中枢神经系统（CNS）产生负面影响并导致CNS疾病。 与柴油机相关的空气污染是全球空气污染的主要贡献者，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残疾和行为异常。特别是，最近的一些研究发现，暴露于与交通有关的空气污染和自闭症谱系障碍（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的原因尚不清楚，虽然它可能具有遗传成分，但环境因素越来越多地被怀疑在其病因学中起关键作用，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，我们发现小鼠围产期暴露于DE（从妊娠第0天到出生后第21天）导致与ASD相关的领域（交流，社交，重复行为）的许多行为改变。本提案的目的是调查可能与ASD相关的发育DE暴露引起的生物化学、分子和形态学改变。特别是，我们将测试的假设，DE诱导的神经炎症将改变信号级联导致，通过表观遗传变化，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，如在ASD。我们还将通过评估在reelin杂合子小鼠（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。rl+/%小鼠将允许直接测试“reelin假说”，并且预期更容易受到DE的影响。Gclm+/%小鼠是一种非常常见的遗传多态性模型，我们已经证明它们对急性DE神经毒性更敏感。总之，这些研究将提供证据的能力DE，作为交通相关的空气污染的指标，导致行为，生化和形态学的改变，这可能是相关的ASD，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.