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.

Public Health Relevance

This project extends previous studies of exposures of young mice to air pollution that revealed aspects of autism spectrum disorder pheontypes. It seeks to examine a more primary set of autism behavioral measures as these were not included in the first set of studies, and to determine whether components of air pollution associated with inflammation, including elemental carbon and endotoxin, each contribute to the phenotype and whether their effects are greater when combined as in air pollution.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Lawler, Cindy P
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University of Rochester
Public Health & Prev Medicine
School of Medicine & Dentistry
United States
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Morris-Schaffer, Keith; Sobolewski, Marissa; Welle, Kevin et al. (2018) Cognitive flexibility deficits in male mice exposed to neonatal hyperoxia followed by concentrated ambient ultrafine particles. Neurotoxicol Teratol 70:51-59
Cory-Slechta, D A; Allen, J L; Conrad, K et al. (2018) Developmental exposure to low level ambient ultrafine particle air pollution and cognitive dysfunction. Neurotoxicology 69:217-231
Klocke, Carolyn; Allen, Joshua L; Sobolewski, Marissa et al. (2018) Exposure to fine and ultrafine particulate matter during gestation alters postnatal oligodendrocyte maturation, proliferation capacity, and myelination. Neurotoxicology 65:196-206
Morris-Schaffer, Keith; Sobolewski, Marissa; Allen, Joshua L et al. (2018) Effect of neonatal hyperoxia followed by concentrated ambient ultrafine particle exposure on cumulative learning in C57Bl/6J mice. Neurotoxicology 67:234-244
Klocke, Carolyn; Allen, Joshua L; Sobolewski, Marissa et al. (2017) Neuropathological Consequences of Gestational Exposure to Concentrated Ambient Fine and Ultrafine Particles in the Mouse. Toxicol Sci 156:492-508
Allen, J L; Klocke, C; Morris-Schaffer, K et al. (2017) Cognitive Effects of Air Pollution Exposures and Potential Mechanistic Underpinnings. Curr Environ Health Rep 4:180-191