持久性有机污染物POPs导致衰老性疾病发生机制的研究

Cellular senescence does contribute to a numbers of organismal aging, can be affected by genetic, epigenetic, environmental factors. Persistent organic pollutants (POPs), which are chemical substances that do not break down in the environment attracted great attention to its effect on environmental pollution and human disease, since man-made chemicals are extensively used recently. Our previous ambispective cohort study showed that, POPs exposure could cause a series of degenerative changes including cells apoptosis, aging of reproductive organs and dysfunction of immune system et.al (n = 7318). At the meanwhile, our data also demonstrated that populations from POPs exposed region have a significantly higher level of DNA damage, increased incidence of telomere shortening and the activation of senescence-associated inflammatory pathway. Moreover, the placenta tissues from the pregnant woman have more SA-β-Gal staining compared to the people from the control area, suggesting that POPs exposure plays an important role in cell senescence and individuals aging. The currently study will explore relationship between POPs exposure and chromosome stability, telomere damage, inflammation, to further clarify the reason why POPs leading to organismal aging and degenerative changes in different tissues, which could finally provide a guide for the therapy involved in environment induced age-related diseases, as well as industrial production and the solid chemical waste disposal.

细胞衰老是个体衰老的关键原因，受遗传、表观遗传、生存状态及环境因素的共同影响。随化工、电子类用品的普遍使用，导致其生产、使用和废弃处理过程中所产生的持久性有机污染物（POPs）造成的环境污染日益严重，对人类健康所造成的不利影响更备受关注。项目组前期队列研究（n=7318）发现，POPs暴露人群出现严重的细胞凋亡及生殖器官衰老、免疫退化等组织退行性改变。同时，现有数据显示暴露人群DNA损伤增加、端粒长度缩短、衰老相关炎性反应通路激活、孕产妇胎盘组织衰老进程加快，证实POPs与细胞和机体衰老密切相关。本项目将系统地研究POPs暴露对染色体稳定性、基因组表观修饰、端粒损伤、炎症反应的影响，明确POPs诱导器官衰老及组织退行性变化的分子机制和信号通路，发现、鉴定个体衰老的预警标志物，为环境诱发的衰老相关疾病的干预方案提供指导，为制定工业生产和固体废弃物无害化处理的标准提供依据。

研究背景：.衰老是一个极为复杂的生物学过程，受到遗传、表观遗传、生活状态饮食习惯以及另外一些随机因素的共同影响。其中环境因素，精神因素是造成衰老的一个重要原因，报道指出水、土壤中的重金属污染，大气中颗粒型污染物的累积均可能造成机体的衰老及器官的退行性变化，而精神压力则可造成衰老的提前发生。明确环境因素、精神因素诱导的衰老性相关疾病的分子机制的研究具有重大的科学价值和社会意义。.研究内容及部分结论：.在本研究中，1）我们构建了环境污染物POPs污染暴露的人群队列，通过队列研究系统的评估POPs可能导致衰老性疾病发生的风险；通过关联分析，评价POPs中对机体衰老及器官退行性变化的产生影响的核心成分；2）构建精神压力，睡眠剥夺的小鼠模型，研究不同精神压力下，机体衰老状态的改变和衰老的分子机制和信号通路；3）通过自主研发衰老通路PCR Array以及二维差异凝胶电泳（2D-DIGE）筛选到一系列个体衰老的预警标志物；4）在分子机制的研究过程中发现，染色质稳定性改变，端粒损伤以及炎症反应均可影响衰老的具体表现。其中CST蛋白的作用极为重要，其突变可造成早老症Coats Plus疾病的发生。.科学意义：.首次证实工业固废拆解过程产生的POPs能够造成胎盘衰老、动脉硬化以及自身免疫功能降低等组织退行性疾病的发生，并伴随人群流产率和新生儿出生缺陷率的急剧升高；第一次提出环境和精神压力可能同时通过端粒DNA长度缩短介导的细胞复制性衰老以及NF-κB激活介导的炎性衰老两个途径影响机体衰老的模型。