燃煤污染型地方性砷中毒发病表观遗传机制及其干预研究

Arseniasis caused by coal-burning is a kind of unique endemic disease that only occurs in our country, which seriously threatens human’s health by causing the injuries and cancers of skin and liver, etc. However, their molecular mechanisms remain unclear and there are few efficient measures of preventing and treating arseniasis caused by coal-burning. Nowadays，although there is increasing attention in epigenetic mechanisms of environment pollution-induced organism injury and carcinogenesis, there are very few investigative publications about the epigenetic mechanisms in arseniasis (including coal-burning type and drinking water type). Based on our preliminary investigations of the population who lived in the endemic area, molecular mechanisms of arsenite-induced cell malignant transformation, and some successful interventions, we are going to investigate the epigenetic mechanisms of intervening DNA damages repair and the malignant transformation induced by immunosuppression-mediated inflammation on three levels including cell, animal, and population, respectively. To investigate the effects of DNA methylation, histones acetylation, and miRNAs on arseniasis caused by coal-burning, we are going to treat the research objects of different systems by the inhibitors, siRNA, high expression plasmids, ginkgo, or SOD-enriched cili juice, respectively. The epigenetic mechanisms and their interventional effects of arseniasis caused by coal-burning will be systematically and deeply investigated on three levels including cell, animal, and population. Our results will be helpful to understand the important roles of epigenetic mechanisms in arsenic-induced multi-organopath, which will provide sciencefic basis to find the early biomarkers, targets, and new intervention strategy of preventing and treating endemic arseniasis.

燃煤型砷中毒是我国独有的严重危害健康的地方病，其主要引起皮肤和肝等脏器损伤及致癌作用，目前发病机制尚不清楚，缺少有效防治措施。环境污染物致机体损伤及致癌作用的表观遗传机制正日益受到重视，而砷中毒（包括饮水型和燃煤型）发病的表观遗传机制研究报道甚少。本项目在长期从事燃煤型砷中毒人群研究及砷致细胞损伤和恶性转化机制研究和获得初步干预成效基础上，从人群、动物和细胞三个层次侧重探讨砷致DNA损伤修复障碍、免疫抑制-炎症反应-恶性转化的表观遗传调控机制；同时应用DNA甲基化、组蛋白乙酰化和miRNAs相关抑制剂、siRNA和甲基供体及高表达质粒、刺梨和银杏制剂等处理不同体系研究对象，从正向和反向在细胞、动物和人群较系统深入地探讨燃煤型砷中毒发病表观遗传机制及干预效果，以揭示表观遗传调控机制在砷致多器官病变中重要作用，为寻找地砷病致机体损伤和致癌作用的早期生物标志和靶标及发现新的干预策略提供科学依据。

燃煤型砷中毒是我国独有的地方病，其主要引起皮肤、肝脏等多器官损伤及癌症高发，其致病机制目前尚不清楚，亦缺少有效的治疗措施。本项目在前期研究基础上，从人群、动物和细胞三个层次探讨砷致机体多器官损伤的表观遗传调控机制；同时应用具有区域特色的银杏和刺梨制剂进行砷中毒干预探索。经过五年的项目实施，获得了一系列研究成果：① 阐明了燃煤型砷中毒病区近20年摄砷途径和砷中毒危险因素变迁。发现燃煤型砷中毒病区外环境砷含量持续下降，但低砷污染依然存在；经消化道摄入取代经呼吸道摄入成为当地人群主要摄砷途径；年龄、吸烟和燃用高砷煤年限始终是燃煤型砷中毒的危险因素。② 明确了燃煤型砷中毒多器官损伤效应类型及其敏感生物学标志。发现燃煤砷暴露可造成机体持续性难可逆免疫功能损伤，还可引起皮肤、肝、肺、肾组织出现明显氧化损伤、DNA损伤或修复抑制；阐明了miR-155与皮肤损伤，miR-21、miR-145与肝损伤，miR-21、miR-191与肺损伤，miR-191与肾损伤存在特异性关联；揭示了4个砷暴露敏感的组蛋白修饰位点：H3K18ac、H3K36me3、H4K20me1和H4K20me2，进一步明确了H3K18ac是燃煤型砷中毒尤其是轻度砷中毒患病风险的敏感位点。③ 通过细胞、动物及人群系列研究，以miRNA、组蛋白修饰及DNA甲基化三大表观遗传调控体系入手，揭示了燃煤型砷中毒多器官（皮肤、肝脏、肺脏、肾脏）损伤的表观遗传网络调控关键靶点及毒性通路，为燃煤型砷中毒早期干预及针对性治疗提供了靶向依据。④ 以发现并验证燃煤型砷中毒的潜在干预靶点及通路为基础，揭示了贵州省天然药植物（银杏制剂、刺梨制剂）对燃煤型砷中毒的干预作用及其机制。本项目的系列研究成果系统阐释了燃煤型砷中毒致病表观遗传调控机制，为新时期针对性防治砷中毒健康损害及优化新的干预策略提供了科学依据。