Air pollution and the brain: gender as an important determinant of susceptibility

空气污染与大脑：性别是易感性的重要决定因素

• 批准号: 9041968
• 负责人: LUCIO G COSTA
• 金额: $ 33.94万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041968
• 关键词: Acute; Adult; Affect; Age; Air Pollutants; Air Pollution; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Astrocytes; Behavior; Behavioral; Brain; Brain region; Bromodeoxyuridine; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cells; Central Nervous System Diseases; Chronic; Coculture Techniques; Corpus striatum structure; Diesel Exhaust; Disease; Encephalitis; Enzymes; Exposure to; Female; Gases; Gender; Gender Role; Genetic; Health; Hippocampus (Brain); In Vitro; Incidence; Inflammation; Knockout Mice; Laboratories; Learning; Lipopolysaccharides; Lung diseases; Measurement; Measures; Memory; Metals; Methods; Microglia; Minocycline; Mitochondria; Morbidity - disease rate; Motor; Motor Activity; Mus; Neuraxis; Neurodegenerative Disorders; Neurons; Outcome; Oxidants; Oxidative Stress; Paraoxonase-2; Particulate Matter; Pathology; Peripheral; Predisposition; Property; Resistance; Respiratory System; Testing; Tissues; Ultrafine; adult neurogenesis; base; cognitive function; differential expression; gender difference; inhibitor/antagonist; male; mortality; motor learning; neurogenesis; neuroinflammation; neurotoxic; neurotoxicity; novel; olfactory bulb; research study; traffic-related air pollution

DESCRIPTION (provided by applicant): The association between air pollution and morbidity and mortality caused by respiratory and cardiovascular diseases is well established; in addition, initial evidence suggests that air pollution may also negatively affect the central nervous system (CNS) and contribute to CNS diseases. Elevated air pollution is associated with decreased cognitive functions and other behavioral alterations, and increased incidence of neurodegenerative disease pathologies. Particulate matter (PM), and in particular ultrafine particulate matter (UFPM; <100 nm), is believed to be the most widespread threat and has been heavily implicated in disease. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component, as it is a major constituent of ambient PM, particularly of UFPM. Few studies in animals have shown that exposure to DE may cause neurotoxicity, with the most prominent effects on the CNS being oxidative stress and neuroinflammation. Among factors which can affect neurotoxic outcomes, gender together with age and genetic background, are considered the most relevant. The general aim of this proposal is to investigate the neurotoxicity of DE, by testing the hypothesis that gender difference in susceptibility exist, with male being more sensitive. This hypothesis is based on recent findings in our laboratory on the enzyme paraoxonase 2 (PON2), an intracellular mitochondrial enzyme, expressed in the CNS, with has potent anti-oxidant properties. PON2 levels are higher in females in all brain regions, and this confers some degree of resistance to oxidants. Preliminary findings in mice upon acute DE exposure are supportive of such hypothesis. The project, articulated in four specific aims, proposes to investigate the neurotoxicity of acute and chronic exposure to DE in male and female mice, with the underlying hypothesis of a higher susceptibility of males. Indicators of oxidative stress, cell death, and microglia activation/neuroinflammation will be measured in brain regions and in peripheral tissues; furthermore the hypothesis that DE-induced neuroinflmmatation will inhibit adult neurogenesis will be tested. Additional studies will investigate olfactory functions, motor activit and learning and memory in DE-exposed mice. Finally, primary neurons from olfactory bulb, hippocampus, and striatum neurons from mice of both genders will be exposed to DE-PM either alone or in the presence of microglia and/or astrocytes to investigate cellular mechanisms of DE neurotoxicity and neuroinflammation.

描述（由申请人提供）：空气污染与呼吸系统和心血管疾病引起的发病率和死亡率之间的关联已得到充分证实；此外，初步证据表明，空气污染还可能对中枢神经系统（CNS）产生负面影响，并导致中枢神经系统疾病。空气污染加剧与认知功能下降和其他行为改变以及神经退行性疾病发病率增加有关。颗粒物 (PM)，特别是超细颗粒物 (UFPM；<100 nm)，被认为是最广泛的威胁，并且与疾病密切相关。与交通相关的空气污染是全球空气污染的主要原因，而柴油机尾气 (DE) 是其最重要的组成部分，因为它是环境 PM，特别是 UFPM 的主要成分。很少有动物研究表明接触 DE 可能会导致神经毒性，其中对中枢神经系统最显着的影响是氧化应激和神经炎症。在影响神经毒性结果的因素中，性别、年龄和遗传背景被认为是最相关的。本提案的总体目的是通过检验存在性别易感性差异（男性更敏感）的假设来研究 DE 的神经毒性。这一假设基于我们实验室对对氧磷酶 2 (PON2) 的最新发现，这是一种细胞内线粒体酶，在中枢神经系统中表达，具有有效的抗氧化特性。女性所有大脑区域的 PON2 水平都较高，这赋予了女性一定程度的抗氧化剂能力。对小鼠急性 DE 暴露的初步研究结果支持了这一假设。该项目有四个具体目标，提议研究雄性和雌性小鼠急性和慢性接触 DE 的神经毒性，其基本假设是雄性小鼠具有更高的易感性。将测量大脑区域和周围组织的氧化应激、细胞死亡和小胶质细胞激活/神经炎症指标；此外，DE 诱导的神经炎症会抑制成体神经发生的假设也将得到检验。其他研究将调查 DE 暴露小鼠的嗅觉功能、运动活动以及学习和记忆。最后，来自两性小鼠的嗅球、海马和纹状体神经元的初级神经元将单独暴露于DE-PM，或者在小胶质细胞和/或星形胶质细胞存在下暴露于DE-PM，以研究DE神经毒性和神经炎症的细胞机制。