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.

摘要 我们在小鼠身上的研究表明，在发育过程中吸入浓缩的环境超细颗粒物 (UFP)空气污染产生的神经病理学和行为特征与3种男性偏见的疾病相同， 也就是说，精神分裂症（SCZ）、自闭症谱系障碍（ASD）和注意缺陷多动障碍（ADHD）， 为越来越多的将这些疾病与空气污染联系起来的流行病学文献提供了生物学上的可信度。在 事实上，在小鼠中观察到的特征与SCZ的特征非常相似。我们的研究并没有特别 用来测试这些连接因此，拟议的申请旨在确定具体的 UFP暴露对SCZ的影响以及引发这些不良影响的机制， 性依赖。目标1检验了以下假设：发育中的UFP暴露将在UFP中产生 浓度依赖性方式，SCZ的经典特征尚未检查（细胞因子的改变） 谱、小清蛋白中间神经元和突触密度的减少以及改变的前脉冲抑制）。SCZ有 与血清铜（Cu）增加有关，并且在小鼠中发现脑Cu水平显着升高， 发育期超微粒子暴露过量的脑铜也可以产生与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Cu污染的升高是UFP的特定驱动因素。 观察到的SCZ特征。脑小胶质细胞定植和激活在男性大脑中较高， 我们的超微粒子暴露期鉴于小胶质细胞活化和炎症在SCZ、ASD和 注意缺陷多动障碍，以及AP和Cu的炎症和氧化还原特性，目的3测试了 小胶质细胞活化作为给予小胶质细胞的雄性动物神经毒性的起始机制 活化抑制剂米诺环素。在青春期，女性大脑表现出更大的小胶质细胞数量/激活 状态因此，目标3还检验了以下假设：青少年接触超微粒子会增加儿童的脆弱性。 女性这些研究的结果有助于确定神经精神疾病的机制， 根据他们的性别差异脆弱性和空气污染的额外监管的潜在需要， 公共卫生保护。