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

描述（由申请人提供）：空气污染与呼吸道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，空气污染也可能对中枢神经系统（CNS）产生负面影响，并导致CNS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，并与疾病密切相关。柴油机相关的空气污染是全球空气污染的主要贡献者，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的主要组成部分。很少有动物研究表明，暴露于DE可能导致神经毒性，对CNS的最显著影响是氧化应激和神经炎症。在可能影响神经毒性结果的因素中，性别以及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易感性存在性别差异（男性更敏感）的假设来研究DE的神经毒性。这一假设是基于我们实验室对对氧磷酶2（PON 2）的最新发现，PON 2是一种细胞内线粒体酶，在CNS中表达，具有有效的抗氧化特性。女性大脑所有区域的PON 2水平都较高，这赋予了对氧化剂一定程度的抵抗力。小鼠急性DE暴露后的初步结果支持这一假设。该项目有四个具体目标，建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的易感性更高。将在脑区和外周组织中测量氧化应激、细胞死亡和小胶质细胞活化/神经炎症的指标;此外，将检验DE诱导的神经炎症将抑制成体神经发生的假设。进一步的研究将调查DE暴露小鼠的嗅觉功能、运动活动以及学习和记忆。最后，将来自两种性别小鼠的嗅球、海马和纹状体神经元的原代神经元单独或在小胶质细胞和/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。

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.