Developmental Exposures to Inhaled Air Pollution and the Autism Phenotype in Mice

 描述(由申请人提供)：现在有多项研究报告空气污染与自闭症谱系障碍(ASD)之间的关联。我们实验室最近的研究出人意料地揭示了ASD的几个特征，这表明这些联系在生物学上是可信的。具体地说，小鼠从出生后4-7天和10-13天(相当于人类晚期妊娠和显著的神经和神经胶质形成时期)暴露到实时道路入口浓缩的环境(10-20x)超细颗粒(UFP，&lt；100 nm)被认为是空气污染中毒性最强的成分，其水平与主要城市的交通繁忙地区一致，因此与人类暴露高度相关，导致持续性的和男性特有的脑室增大，穹隆体部发育中断，小胶质细胞激活增加以及冲动和重复行为，在两性中，大脑谷氨酸水平上升，学习和短期记忆受损，所有这些特征都在ASD中报道。因为这些研究中的行为测试先于神经病理改变，所以没有对原发ASD行为缺陷进行检查。拟议的应用寻求在假设的背景下检查更广泛的ASD样行为以及炎症、神经病理和神经化学后果，即空气污染可能通过其有机(内毒素)和无机(碳)成分引发的炎症事件来调节ASD表型的风险，当有机(内毒素)和无机(碳)成分共存时，这些炎症事件可以相加甚至协同作用。因此，在小鼠吸入高浓度超细环境颗粒物、超细元素碳、内毒素和复合超细颗粒物的反应中，将检查ASD样行为、神经病理变化、兴奋-抑制平衡和炎症标志物的广泛变化。 元素碳和内毒素，在人类空气污染暴露的条件下会发生。这一假设的确认将为这一模型提供必要的生物学有效性，并为随后的机制路径评估奠定基础，包括那些潜在的性依赖、与自闭症相关基因的相互作用以及脆弱的关键时期。确定应负责任的污染物成分对公共卫生保护和监管政策至关重要。

 DESCRIPTION (provided by applicant): Multiple studies now report associations of air pollution with autism spectrum disorder (ASD). Recent studies from our laboratory unexpectedly revealed several features of ASD suggesting biological plausibility for these associations. Specifically, exposures of mice from postnatal days (PND) 4-7 and 10-13, equivalent to human third trimester and a period of marked neuro- and gliogenesis, to real time, road inlet concentrated ambient (10-20x) ultrafine particles (UFP, <100 nm), considered the most toxic component of air pollution, at levels consistent with high traffic areas of major cities and thus highly relevant to human exposures resulted in persistent and male-specific ventriculomegaly, disrupted corpus callosum development, increases in microglial activation and in impulsive and repetitive behaviors, and in both sexes, increased brain glutamate levels and impaired learning and short-term memory, all features reported in ASD. Because behavioral testing in those studies preceded the neuropathological alterations, primary ASD behavioral deficits were not examined. The proposed application seeks to examine a broader array of ASD-like behaviors as well as inflammatory, neuropathological and neurochemical consequences in the context of the hypothesis that air pollution may contribute risk for the ASD phenotype as mediated by inflammatory events arising from its organic (endotoxin) and inorganic (carbon) components that could act additively or even synergistically when co-occurring. Changes in a broad profile of ASD-like behaviors, neuropathological changes, excitatory- inhibitory balance and markers of inflammation will thus be examined in response inhalational exposures of mice to concentrated ultrafine ambient particles, to ultrafine elemental carbon, to endotoxin, and to combined ultrafine elemental carbon and endotoxin as would occur under conditions of human air pollution exposures. Confirmation of this hypothesis would provide the requisite biological validity to this model and establish a base for subsequent assessments of mechanistic pathways, including those underlying sex-dependencies, interactions with autism- relevant genes and critical periods of vulnerability. Identification of responsible component pollutants is critical to public health protection and to regulatory policies.