Air Pollution and Male-Biased Psychiatric Disorders

空气污染和男性偏向的精神疾病

• 批准号: 10265538
• 负责人: Deborah A Cory-Slechta
• 金额: $ 41.01万
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265538
• 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; schizophrenia risk; 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.

抽象的 我们对小鼠的研究表明，在发育过程中吸入暴露于浓缩的环境超细颗粒 (UFP) 空气污染会产生 3 种偏向男性的疾病所共有的神经病理学和行为特征， 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）， 为越来越多的流行病学文献提供了生物学上的合理性，将这些疾病与空气污染联系起来。在 事实上，在小鼠身上观察到的特征与 SCZ 的特征非常相似。我们的研究并不是专门 旨在测试这些连接。因此，拟议的申请旨在确定具体的 发育性 UFP 暴露于 SCZ 的贡献以及引发这些不利影响的机制以及 他们的性别依赖性。目标 1 检验发育性 UFP 暴露将产生的假设，在 UFP 中 浓度依赖性方式，SCZ 的经典但未经检验的特征（细胞因子的改变） 特征、小白蛋白中间神经元和突触密度的减少以及预脉冲抑制的改变）。 SCZ 有 与血清铜 (Cu) 增加有关，并且在小鼠体内发现铜水平显着升高 发育性 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，目标 2 检验了以下假设：环境 UFP 中铜污染升高是导致 观察到的 SCZ 特征。男性大脑中的小胶质细胞定植和激活程度较高 我们的 UFP 暴露期。鉴于小胶质细胞激活和炎症在 SCZ、ASD 和 ADHD 以及 AP 和 Cu 的炎症和氧化还原特性，Aim 3 测试了 小胶质细胞活化作为男性神经毒性的起始机制 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 状态。因此，目标 3 还检验了青少年 UFP 暴露会增加青少年脆弱性的假设。 女性。这些研究的结果有助于确定神经精神疾病的机制和 其脆弱性因性别而异，并且可能需要对空气污染进行额外监管 公共卫生保护。