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.

Public Health Relevance

Increasing evidence suggests that traffic1related air pollution may negatively affect the central nervous system (CNS), particularly when exposure occurs in the perinatal period, thus contributing to neurodevelopmental disorders. Aim of this project is to investigate the neurotoxicity of developmental diesel exhaust (DE) exposure in mice, with a combination of behavioral, biochemical, and morphological approaches, with emphasis on end-points related to autism spectrum disorders (ASD). An important aspect of the proposal is the study of gene1environment interactions, which will be tested in transgenic mouse models exposed to DE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES028273-01
Application #
9358989
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Lawler, Cindy P
Project Start
2017-09-01
Project End
2022-07-31
Budget Start
2017-09-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Washington
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chang, Yu-Chi; Cole, Toby B; Costa, Lucio G (2018) Prenatal and early-life diesel exhaust exposure causes autism-like behavioral changes in mice. Part Fibre Toxicol 15:18
Costa, Lucio G; Chang, Yu-Chi; Cole, Toby B (2017) Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism. Curr Environ Health Rep 4:156-165
Chang, Yu-Chi; Cole, Toby B; Costa, Lucio G (2017) Behavioral Phenotyping for Autism Spectrum Disorders in Mice. Curr Protoc Toxicol 72:11.22.1-11.22.21