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

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 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.