Grx/Trx系统的交互对话在砷致肝损伤中的作用和机制研究

Endemic arsenicosis is a public health concern which seriously threats to the health of rural residents. High arsenic exposure would damage to other organs before skin lesions, however, it does not attract extensive attention because of its non-specific symptoms and concealed development. At present, study shows that liver is the target organ of carcinogenic induced by arsenic, but the mechanisms of arsenic-induced liver toxicity have not yet been fully understood. Oxidative damage could be one of the major mechanisms. Applicants firstly found that water arsenic exposure can cause some changes in human serum Trx1. There were positive correlations not only between Trx1 content in serum and total arsenic intake, but also between serum Trx1 concentration and different forms of urinary arsenic levels, which suggested that Trx1 can be used as early effect biomarker in the human before the skin lesions. Therefore, we propose a scientific hypothesis as followings: Grx/Trx systems cross-talk via the mechanisms of resisting oxidative stress and inducing apoptosis involve in arsenic-induced liver injury. The present study will prove this hypothesis, through cross-sectional survey to analyse the relationship between Grx/Trx systems & index of oxidative stress and arsenic exposure, and the depletion of GSH by treatment with BSO to build the model of rat liver injury. It is very important to clarify the mechanism of arsenic-induced liver injury, 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。高砷暴露在导致机体出现皮肤损伤之前，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。目前，研究显示肝脏是砷致癌的靶器官之一，但砷对肝脏毒性作用的确切机制尚不清楚，其中氧化损伤是主要的学说之一。申请者前期研究首次发现：水砷暴露能引起人体血清Trx1的改变，血清Trx1含量和总水砷摄入量、不同形态尿砷水平都存在正相关，说明Trx1可以作为皮肤损伤前的早期有效的生物标志物。在此基础上，提出Grx/Trx系统的交互对话通过抗氧化应激以及诱导细胞凋亡参与砷致肝损伤机制的假设。本研究将通过人群现况调查分析Grx/Trx系统及相应氧化应激指标与砷暴露的相关性，以及利用BSO干预消耗GSH来制备大鼠肝损伤模型从而证明上述假设。这对于阐明砷致肝脏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。砷进入机体后，主要蓄积于肝脏，并可通过多种途径引起不同程度的肝损伤、肝纤维化、肝硬化及肝癌。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，揭示砷暴露与人群肝损伤的关系，以及探讨Grx/Trx系统在砷暴露导致的人群肝功能异常中的作用；通过利用BSO干预消耗GSH来制备大鼠肝损伤动物模型，观察不同程度砷暴露对大鼠肝损伤程度，分析砷暴露对大鼠肝组织Grx/Trx系统交互对话的影响，采用定量PCR、蛋白印迹、免疫组化等技术研究Grx/Trx系统的交互对话在砷致肝损伤的机制。. 本研究的主要结果如下：. 1. 慢性高砷暴露人群同非高砷暴露人群相比更易发生肝损伤；. 2. 中、高砷暴露人群中血清总蛋白、白蛋白含量明显低于非高砷暴露人群；. 3. 中、高砷暴露可能通过抑制肝合成功能、促进胆汁酸排泄功能导致肝损伤；. 4. 急性砷暴露可以影响大鼠的肝功能，并能导致肝脏病理形态发生改变；. 5. 高砷+BSO联合组明显耗竭体内GSH，可能使机体对活性氧和自由基的防御作用能力下降；. 6. Grx/Trx系统基因和蛋白表达均上调，呈现剂量反应关系，说明急性砷暴露能导致大鼠肝组织发生氧化应激反应，使肝组织中Grx/Trx系统过表达；. 7. Grx/Trx系统可能共同参与砷致肝损伤的氧化应激机制，Trx系统可能在该机制中占主导作用。.