苯并[a]芘对神经退行性病变的毒性作用与机制研究

The contribution of exposure to enviromental risk factors and inflammatoion to the pathogenesis of Alzheimer's disease (AD,the most common neurodegenerative disease) has been increasingly appreciated. Benzo[a]pyrene, B[a]P, a polycyclic aromatic hydrocarbon and well-known micropollutant in the environment, has immune toxicity and neurodevelopmental toxicity, bescides its probable carcinogen and teratogenicity in humans. Inhalation of polluted air or ingestion of contaminated food (especially grilled, roasted or smoked) or water can lead to B[a]P exposure. Recently, B[a]P exposure has been reported to be associated with memory decline in professional worker and experimental rats. In addition, Tau hyperphosphorylation has been shown to be associated with spatial learning and memory after exposure to B[a]P in SD rats. As the industrization and the consequentant growing air pollution in China, expeically the increasing production of B[a]P from industrial and automobile exhaust fumes, cigarette smoke, manufacturing of products such as coal, tar, asphalt, petroleum, and charcoal-broiled, fried, roasted and smoked foods, it becomes urgent to investigate whether chronic exposure to B[a]P increases the risk of the development of Alzheimer's disease. Using both in vitro and in vivo systems, we will will investigate how chronic B[a]P exposure affects neuronal survival and microglia activaton (the key feature of brain inflammation). We will also study how interactions of B[a]P exposure and gene mutations affect the development of Alzheimer's disease pathogenesis and to elucidate its underlying mechanisms. Importnatly, we plan to use genetically engineered mice and cell cultures to investigate the cellular and molecular mechanism by which B[a]P exposure interacts with brain immune cells microglia to affect communication between neurons and microglia and development of Alzheimer's disease. Results from these studies will uncover environmental risk facotrs for Alzheimer's disease, identify novel anti-inflammatory therapeutic target and shed new insight into the immune toxicity and neurotoxicity of B[a]P exposure. Further development and screening of anti-inflammatory and neuroprotective drugs targeting the identified target(s) identified by this project will provide important mechanistic basis for translational medicine for future clinical trails for neurodegenerative diseases.

阿尔兹海默症（AD, 又称老年痴呆症）的环境致病因素和炎性发病机制渐被重视。五环芳香烃苯并[a]芘除了致癌和致畸性,也表现免疫毒性和神经发育毒性，特别是导致职业暴露工人和实验大鼠记忆能力下降和实验鼠脑内Tau蛋白超磷酸化。随着我国大气污染的日益严重，尤其是煤，石油，烟草等不完全燃烧释放大量苯并[a]芘，目前亟待深入研究慢性苯并[a]芘暴露是否增加AD发病风险。本项目以前期原创发现为基础，通过体外实验到小鼠整体水平，系统地研究慢性苯并[a]芘暴露1）对神经存活和脑内小胶质细胞激活的作用，2）与突变基因相互做用对AD发病的作用和机理，3）在整体动物对神经炎症和AD特征性病理变化（Tau超磷酸化和β-amyloid聚集等）和记忆认知功能障碍的作用和机制。本项目对阐明AD病因提供重要研究工具和线索，为AD病因研究和神经损伤的预防治疗提供理论依据，为研发该病的新型治疗策略提供新靶点。

本项目着重于阐述了苯并[a]芘在神经退行性疾病发生发展中的作用与相关机制研究，为深入了解神经退行性疾病的病理发展提供了理论基础，并发现并验证了包括NADPH氧化酶及通道蛋白Cx43等在内的重要毒性靶点及通路，为此类疾病的预防或治疗提供新的依据。近几年来的这些重要发现已得到了神经毒理学界的广泛认可，包括：1）大气颗粒物中有机组分或农药等在其颗粒物神经毒性中的作用和机制；2）首次系统发现了环境污染物苯并[a]芘在阿尔兹海默症及帕金森病形成中的作用与机制；3）在脑胶质细胞重要作用的提示下，首次利用中脑定位注射干预方式发现通道蛋白Cx43被抑制对帕金森病小鼠的神经保护作用并探讨了相关机制。前两方面的研究深化了对苯并[a]芘神经毒性的了解，并发现了其主要作用靶点与通路，为大气污染暴露尤其是苯并[a]芘的健康防护及临床预警提供了理论基础，达到国际一流的研究水平，具有显著的社会价值。第三方面在小鼠及细胞的研究中抑制Cx43均发现了令人印象深刻的多巴胺神经元保护功能，提示了其成为新的治疗性靶点的可能性以及其多肽抑制剂潜在的药物开发前景，具有巨大的应用潜力。