title: Developmental neurotoxicity of inhaled ambient ultrafine particle air pollution: Parallels with neuropathological and behavioral features of autism and other neurodevelopmental disorders.
abstract: Accumulating evidence from both human and animal studies show that brain is a target of air pollution. Multiple epidemiological studies have now linked components of air pollution to diagnosis of autism spectrum disorder (ASD), a linkage with plausibility based on the shared mechanisms of inflammation. Additional plausibility appears to be provided by findings from our studies in mice of exposures from postnatal day (PND) 4-7 and 10-13 (human 3rd trimester equivalent), to concentrated ambient ultrafine (UFP) particles, considered the most reactive component of air pollution, at levels consistent with high traffic areas of major U.S. cities and thus highly relevant to human exposures. These exposures, occurring during a period of marked neuro- and gliogenesis, unexpectedly produced a pattern of developmental neurotoxicity notably similar to multiple hypothesized mechanistic underpinnings of ASD, including its greater impact in males. UFP exposures induced inflammation/microglial activation, reductions in size of the corpus callosum (CC) and associated hypomyelination, aberrant white matter development and/or structural integrity with ventriculomegaly (VM), elevated glutamate and excitatory/inhibitory imbalance, increased amygdala astrocytic activation, and repetitive and impulsive behaviors. Collectively, these findings suggest the human 3rd trimester equivalent as a period of potential vulnerability to neurodevelopmental toxicity to UFP, particularly in males, and point to the possibility that UFP air pollution exposure during periods of rapid neuro- and gliogenesis may be a risk factor not only for ASD, but also for other neurodevelopmental disorders that share features with ASD, such as schizophrenia, attention deficit disorder, and periventricular leukomalacia.
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, United States. Electronic address: joshua_allen@urmc.rochester.edu.
authors.forename: J L
authors.initials: JL
authors.lastname: Allen
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, United States.
authors.forename: G
authors.initials: G
authors.lastname: Oberdorster
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, United States.
authors.forename: K
authors.initials: K
authors.lastname: Morris-Schaffer
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, United States.
authors.forename: C
authors.initials: C
authors.lastname: Wong
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, United States.
authors.forename: C
authors.initials: C
authors.lastname: Klocke
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, United States.
authors.forename: M
authors.initials: M
authors.lastname: Sobolewski
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, United States.
authors.forename: K
authors.initials: K
authors.lastname: Conrad
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, NY 14642, United States.
authors.forename: M
authors.initials: M
authors.lastname: Mayer-Proschel
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, United States.
authors.forename: D A
authors.initials: DA
authors.lastname: Cory-Slechta
mesh_terms: D000397:Air Pollution / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D001321:Autistic Disorder / Q000209:etiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003337:Corpus Callosum / Q000473:pathology; D003760:Dental Impression Materials / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D020547:Lateral Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D052638:Particulate Matter / Q000633:toxicity; D012828:Silicones / Q000009:adverse effects*
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D003760:Dental Impression Materials; D008840:Microfilament Proteins; D004676:Myelin Basic Protein; D018377:Neurotransmitter Agents; D052638:Particulate Matter; D012828:Silicones
keywords: Air pollution; Autism; Corpus callosum; Excitatory–inhibitory imbalance; Lateral ventricle; Myelination; Periventricular leukomalacia; Schizophrenia; Ultrafine particles; White matter