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Air Pollution and Male-Biased Psychiatric Disorders

空气污染和男性偏向的精神疾病

基本信息

批准号：
10065880
负责人：
Deborah A Cory-Slechta
金额：
$ 41.4万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-18 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10065880
关键词：
Adolescence Adolescent Adverse effects Air Pollution Animal Model Animals Attention deficit hyperactivity disorder Attenuated Behavior Behavioral Biochemical Biological Brain Brain region Characteristics Cognitive Cognitive deficits Copper Corpus Callosum Dependence Development Disease Dopamine Environmental Risk Factor Epidemiology Etiology Exhibits Exposure to Female Glutamates Health protection Human Impairment Impulsivity Inflammation Inflammatory Inhalation Inhalation Exposure Interneurons Intervention Link Literature Mediating Mental disorders Metals Microglia Minocycline Motor Mus Mutation Neurodevelopmental Disorder Neurons Oxidation-Reduction Oxides Parvalbumins Pattern Phenotype Property Public Health Regulation Reporting Risk Risk Factors Role Schizophrenia Sensory Serum Sex Differences Stimulus Symptoms Synapses Testing air contaminant autism spectrum disorder base cytokine density design emerging adult epidemiology study gray matter high risk human model inhibitor/antagonist lateral ventricle male myelination nanoparticle neuropathology neuropsychiatric disorder neurotoxic neurotoxicity particle exposure postnatal prepulse inhibition response risk minimization sex social synaptic pruning ultrafine particle white matter

项目摘要

Abstract Our studies in mice show that inhaled exposures during development to concentrated ambient ultrafine particle (UFP) air pollution produces neuropathological and behavioral features common to 3 male-biased disorders, i.e., schizophrenia (SCZ), autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), providing biological plausibility to a growing epidemiological literature linking these disorders to air pollution. In fact, the observed features in mice are intriguingly similar to those of SCZ. Our studies were not specifically designed to test these connections. Therefore, the proposed application seeks to determine the specific contribution of developmental UFP exposures to SCZ and the mechanisms initiating these adverse effects and their sex-dependency. Aim 1 tests the hypothesis that developmental UFP exposures will produce, in a UFP concentration-dependent manner, classic as yet unexamined characteristics of SCZ (alterations in cytokine profiles, reductions in parvalbumin interneurons and synaptic density and altered pre-pulse inhibition). SCZ has been linked to increased serum copper (Cu), and markedly elevated brain Cu levels in mice were found after developmental UFP exposure. Excess brain Cu can also produce neurotoxic features consistent with SCZ. Consequently, Aim 2 tests the hypothesis that elevated Cu contamination in ambient UFP is a specific driver of the observed SCZ features. Brain microglial colonization and activation is higher in male brain during the period of our UFP exposures. Given the critical role of microglial activation and inflammation in SCZ, ASD and ADHD, and the inflammatory and redox properties of AP and of Cu, Aim 3 tests the mechanistic role of microglial activation as the initiating mechanism of neurotoxicity in males by administration of the microglial activation inhibitor, minocycline. During adolescence, female brain exhibits greater microglial number/activation state. Thus, Aim 3 also tests the hypothesis that adolescent UFP exposure will enhance vulnerability of females. Findings from these studies assist in defining mechanisms for neuropsychiatric disorders and the basis of their differential vulnerability by sex and a potential need for additional regulation of air pollution for public health protection.

摘要