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

描述(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联系已经确立；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CNS疾病。空气污染加剧会导致认知功能下降和其他行为改变，并增加神经退行性疾病的发病率。颗粒物(PM)，特别是超细颗粒物(UFPM；&lt；100 nm)被认为是最广泛的威胁，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贡献者，而柴油废气(DE)是其最重要的组成部分，因为它是环境PM的主要组成部分，特别是UFPM。很少有动物研究表明，暴露于DE可能会导致神经毒性，对中枢神经系统最显著的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。这项建议的总体目的是通过检验性别易感性存在差异的假设来研究DE的神经毒性，男性更敏感。这一假说是基于我们实验室最近对对氧磷酶2(PON2)的发现，对氧磷酶2是一种在中枢神经系统表达的细胞内线粒体酶，具有强大的抗氧化特性。女性大脑所有区域的PON2水平都较高，这赋予了女性对氧化剂一定程度的抵抗力。在急性DE暴露的小鼠身上的初步发现支持这一假设。该项目有四个具体目标，建议调查雄性和雌性小鼠急性和长期暴露于DE的神经毒性，潜在的假设是雄性小鼠的易感性更高。氧化应激、细胞死亡和小胶质细胞激活/神经炎症的指标将在大脑区域和外周组织中进行测量；此外，将测试DE诱导的神经炎症将抑制成人神经发生的假设。其他研究将调查暴露于DE的小鼠的嗅觉功能、运动激活以及学习和记忆。最后，来自嗅球、海马体和纹状体神经元的原代神经元将单独或在小胶质细胞和/或星形胶质细胞存在的情况下暴露于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.