同型半胱氨酸(Hcy)在砷致认知功能损伤中的作用及其分子机制研究

Endemic arsenicosis is a public health concern which seriously threats to the health of rural residents, is also one of the endemic diseases with important prevention and control in China. High arsenic exposure would damage to other organs before appearing "trilogy of skin", however, it does not attract extensive attention because of its non-specific symptoms and concealed development. In recent years, it is well known that arsenic is a nerve poisoning element, which exerts bad effect on the central nervous system of exposed population, and causes cognitive impairment, however, currently the mechanism is unclear. Applicants found that the plasma homocysteine(Hcy) levels of high arsenic exposure groups increased significantly in previous studies on biomarkers of arsenic poisoning, therefore we propose a scientific hypothesis as followings: arsenic can increase the Hcy levels of body in the process of methylation, inhibits NOS activity through the way of DDAH/ADMA, reduces NO, and directly causes to decrease of neuronal LTP; and can also down the expression of CREB by the way of PTEN/PI3K/Akt, eventually lead to neuronal injury. The present study will prove this hypothesis, through cross-sectional survey of large sample size, case-control study, cohort study, and combined with the animal experiments. It is very important to clarify the mechanism of arsenic-induced cognitive impairment, and this study may provide a new theory for the prevention and control of arsenic poisoning in future.

地方性砷中毒是一个严重危害广大农村居民身体健康的公共卫生问题，是我国重点防治的地方病之一。高砷暴露在导致机体出现"皮肤三联症"之前，即可引起其他组织器官的损伤，但因损伤不特异、发病隐匿而并未引起广泛重视。近年来，砷作为一种神经毒物，能够对暴露人群的中枢神经系统造成损害并导致认知功能障碍已经被广大学者所关注和认可，但机制尚不清楚。申请者在以往研究砷中毒生物标志的工作中发现，高砷暴露人群血浆Hcy水平增高明显，在此基础上，提出以下科学假设：砷在甲基化代谢过程中使机体Hcy含量增加，通过DDAH/ADMA途径抑制NOS活性，致NO减少，既可直接导致神经元LTP下降，又可通过PTEN/PI3K/Akt途径下调CREB表达，进而导致神经元损伤。本研究拟通过大样本量现况调查、病例对照以及队列研究，结合动物实验证明上述假设。这对于阐明砷致认知功能损伤机制具有重要的意义，将为砷中毒的防治提供新的科学理论。

地方性砷中毒是我国重点防治的地方病之一。砷作为一种神经毒物，能够对暴露人群的中枢神经系统造成损害并导致认知功能障碍。本研究通过对饮水型砷中毒病区暴露于不同砷水平的人群进行现场流行病学调查，揭示砷暴露与人群认知损伤的关系，以及探讨造成认知损伤的危险因素；通过建立砷暴露动物模型，采用定量PCR、蛋白印迹、免疫组化等技术研究砷暴露与神经系统损伤的关系。本研究取得的主要成果如下：.1.慢性高砷暴露人群同非高砷暴露人群相比认知功能明显下降；.2.高砷暴露人群中血浆同型半胱氨酸浓度明显高于非高砷暴露人群；.3.高砷暴露增加了认知功能损伤及高同型半胱氨酸血症发生的危险度；.4.慢性砷暴露可以降低大鼠学习记忆能力；.5.慢性砷暴露大鼠血清同型半胱氨酸水平升高，去除砷暴露后其水平可恢复正常；.6.砷暴露可通过调控PTEN-Akt-CREB信号通路，导致神系统细胞损伤；.7.砷暴露可通过激活大鼠脑组织Fas/FasL信号传导通路诱导大鼠神经细胞凋亡；.8.慢性砷暴露可能通过激活大鼠脑组织内质网应激途径诱导大鼠神经细胞凋亡。