Air Pollution and Male-Biased Psychiatric Disorders

空气污染和男性偏向的精神疾病

• 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
• 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

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 我们在老鼠身上的研究表明，在发育过程中吸入环境中浓缩的超细颗粒物 (UFP)空气污染会产生3种男性偏向疾病共同的神经病理和行为特征， 即精神分裂症(SCZ)、自闭症谱系障碍(ASD)和注意力缺陷多动障碍(ADHD)， 越来越多的流行病学文献将这些疾病与空气污染联系在一起，为其提供了生物学上的合理性。在……里面 事实上，在小鼠身上观察到的特征与SCZ的特征有趣地相似。我们的研究并不是特别的 旨在测试这些连接。因此，拟议的申请寻求确定具体的 发育期UFP暴露对SCZ的贡献及其引发这些不良影响的机制 他们的性依赖。AIM 1测试发育中的UFP暴露将在UFP中产生的假设 浓度依赖方式，经典的SCZ尚未检查的特征(细胞因子的变化 小白蛋白中间神经元和突触密度的减少以及脉冲前抑制的改变)。SCZ有 与血清铜(铜)增加有关，并发现小鼠脑内铜水平显著升高 发育期UFP暴露。过量的脑铜也会产生与SCZ一致的神经毒性特征。 因此，Aim 2测试了这样的假设，即周围UFP中铜污染的增加是导致 观察到的SCZ特征。男性脑内小胶质细胞定植和活化程度较高 我们的UFP曝光期。鉴于小胶质细胞活化和炎症在SCZ、ASD和 ADHD，以及AP和Cu的炎症和氧化还原特性，Aim 3测试了Ap的机制作用 小胶质细胞激活是小胶质细胞对男性神经毒性的启动机制 激活抑制剂，米诺环素。在青春期，女性大脑表现出更多的小胶质细胞数量/激活 州政府。因此，Aim 3还验证了青少年接触UFP会增加其易感性的假设 女性。这些研究的发现有助于确定神经精神障碍的机制和 按性别区分脆弱性的依据，以及可能需要对空气污染进行额外监管 公共卫生保护。