CNS Toxicity of Ambient Air Pollution: Postnatal Exposure to Ultrafine Particles

描述（由申请人提供）： 越来越多的证据表明，空气污染物如超细颗粒物（UFP）对肺部的炎症/细胞因子激活作用也可能发生在大脑中。事实上，基于这些机制，UFP可能会产生类似于母体/新生儿炎症的CNS效应，其成分被认为是精神分裂症，自闭症脑瘫，精神发育迟滞和帕金森病的模型。与这种可能性相一致，本文提供的初步数据表明，出生后UFP暴露导致小鼠成年后腹侧中脑和海马体的持续脑炎症，这些脑区域是介导复杂认知和运动功能的关键。这种残余炎症表明，发育中的UFP暴露可能是迄今为止儿童神经发育功能障碍的一个未被充分认识的风险因素，或者是神经退行性疾病的一个胎儿风险因素。为了评估这种可能性，本文提出的实验测试以下假设：1）基于海马和腹侧中脑的持续损伤，这些相同的出生后UFP暴露将在小鼠的认知和运动功能中产生性别特异性损伤;和2）行为损伤将与脑细胞因子、炎症、氧化应激、神经递质和/或血浆皮质酮水平的改变相关。行为评估将包括学习、冲动和工作记忆的测量，以提供对这些认知领域的相对敏感性的评估，还将包括随时间推移的运动活动的个体发育特征。类似地，炎症、细胞因子活化、氧化应激和神经递质变化的多种标志物的纵向测定认识到多种机制的潜力，并将提供关于行为变化的潜在机制基础的初始信息。积极的研究结果将建立广泛扩展的研究，包括其他空气污染物暴露与潜在的大脑影响（臭氧），组合暴露，暴露的发育期的作用，机制，外周超微粒激活脑细胞因子等的基础上，这些研究可能会导致重大进展，了解空气污染物的神经发育和神经退行性疾病的病因。 公共卫生相关性： 越来越多的证据表明，超细颗粒（UFP）空气污染可能会导致持续的脑部炎症。拟议的可行性研究将测试小鼠的发育UFP暴露是否会影响认知和/或运动行为，以及它们被破坏的机制。积极的发现表明，UFP代表了以前未被充分认识的脑功能障碍的基础。

DESCRIPTION (provided by applicant): Increasing evidence suggests that the inflammation/cytokine activating effects of air pollutants such as ultra fine particles (UFP) on lung may also occur in brain. In fact, based on such mechanisms, UFP might be predicted to produce CNS effects similar to those seen with maternal/neonatal inflammation, components of which are considered models of schizophrenia, autism cerebral palsy, mental retardation and Parkinson's disease. Consistent with this possibility, preliminary data presented here shows that postnatal UFP exposures results in sustained brain inflammation in mice as adults in ventral midbrain and hippocampus, brain regions key to mediating complex cognition and motor functions. Such residual inflammation suggests that developmental UFP exposure may represent a heretofore largely underappreciated risk factor for neurodevelopment dysfunction in children or a fetal risk factor for neurodegenerative diseases. To evaluate this possibility, experiments proposed here test the hypotheses that: 1) based on sustained damage to hippocampus and ventral midbrain, these same postnatal UFP exposures will produce gender-specific impairments in mice in cognitive and motor functions; and 2) behavioral impairments will be related to alterations in levels of brain cytokines, inflammation, oxidative stress, neurotransmitters and/or plasma corticosterone. Behavioral assessment will include measures of learning, impulsivity and working memory to provide an assessment of comparative sensitivity across these cognitive domains, and will also include the ontogenic profile of locomotor activity across time. Similarly, the longitudinal determination of multiple markers of inflammation, cytokine activation, and oxidative stress and neurotransmitter changes recognizes the potential for multiple mechanisms and will provide initial information on potential mechanistic bases of behavioral changes. Positive findings would establish the basis for a broad expansion of research to include other air pollutant exposures with potential brain impacts (ozone), combined exposures, role of developmental period of exposure, mechanisms by which peripheral UFP activates brain cytokines, etc. Such studies could lead to significant advances in understanding the contribution of air pollutants to the etiology of neurodevelopment and neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: Increasing evidence suggests that ultrafine particle (UFP) air pollution may produce sustained brain inflammation. The proposed feasibility studies will test whether developmental UFP exposures of mice can affect cognitive and/or locomotor behavior, and mechanisms by which they are disrupted. Positive findings would suggest that UFP represents a previously underappreciated basis for brain dysfunction.