高环境暴露风险金属纳米材料诱发骨髓单核细胞发育毒性的作用机制

Environmental exposure and toxicological impacts of nanomaterials have raised great concerns. However, only limited studies demonstrated the toxicity of nanomaterials due to their environmental/biological transformation. Given the key issues related to nanomaterial-induced environmental and health risks, we plan to focus on metal nanomaterials with broad applications, high exposure risk as well as large production and consumption, including nano silver particles, nano TiO2 particles, and ZnO. Thereafter, we endeavor to verify the environmental/biological transformation and bioavailability of nanomaterials, to illuminate their toxicity to myelomonocyte development, and to investigate the effects of environmental and biological transformation on myelomonocyte development toxicity. We also embark on identifying the functional pathways and molecular mechanisms responsible for the impairments to myelomonocyte formation, differentiation, maturation and immunoregulatory function upon metal nanomaterial administration. Research contents: a) main physicochemical characteristics and environmental elements related to changes in bioavailability for metal nanomaterials; b) identification of myelomonocyte developmental toxicity following metal nanomaterial exposure under environmental exposure settings; c) molecular mechanisms of myelomonocyte developmental toxicity and according features in response to environmental transformation. Key scientific issues: a) determinal relationship between environmental/biological transformation of nanomaterials and myelomonocyte developmental toxicity; b) molecular mechanisms and toxicity pathways underlying nanomaterial-induced myelomonocyte developmental toxicity from the perspectives of developmental cycle and immunological function. This study would be of great importance in recognizing the potential risks of metal nanomaterials to the environment and human health.

纳米材料的环境健康问题日益备受关注。目前对于纳米材料环境与生物转化相关毒性的研究匮乏，而环境/生物转化决定了其环境暴露与毒性效应。为此本项目选择应用范围广、产量和使用量大的高环境暴露风险金属纳米材料（纳米银、纳米TiO2和纳米ZnO等）为重点研究对象，明确环境暴露下纳米材料的转化与生物有效性，揭示环境与生物转化对骨髓单核细胞发育毒性的影响机制，并明确其影响单核细胞发育、分化、成熟及免疫调节功能的作用特征及分子机制。研究内容：⑴影响金属纳米材料对造血器官骨髓的生物有效性的关键理化性质与环境因素；⑵金属纳米材料导致单核细胞发育毒性的特征；⑶金属纳米材料诱发单核细胞发育毒性的作用机制。拟解决的关键科学问题：⑴决定金属纳米材料对骨髓生物有效性的关键理化性质与环境条件；⑵金属纳米材料导致单核细胞发育毒性的主要发育阶段、功能损伤特征以及毒性通路。本研究对于识别金属纳米材料的环境健康风险具有科学价值。

纳米材料的人群暴露风险及健康危害日益备受关注。进入机体的纳米颗粒，会通过血液循环系统到达周身各处并与各种血细胞发生直接的相互作用。纳米颗粒对单核-巨噬细胞系统的直接或间接损伤是影响机体免疫内环境稳态，诱发组织病理损伤的关键。因此，探究金属纳米材料对骨髓单核细胞的发育毒性效应及机制具有重要环境健康意义。本项目拟解决的核心科学问题是：纳米颗粒损伤单核细胞的毒理机理及关键理化性质。重点关注：影响纳米颗粒体内归趋、富集等生物有效性的关键理化性质和环境因素，纳米颗粒对单核细胞的毒性效应及免疫调节功能影响的分子机制。.本项目研究成果主要创新点：.1.揭示影响纳米金诱导树突状细胞成熟、活化的关键理化性质。发现纳米金表面修饰特征显著影响其与细胞的相互作用，设计、合成不同表面配体小分子修饰球型纳米金颗粒库，获得能够显著活化树突状细胞的纳米金颗粒。.2.阐明纳米金颗粒物影响树突状细胞功能活性的主要机制。发现纳米金颗粒表面配体与树突状细胞膜表面的TLR4受体的直接结合以及其所介导的通路的激活，导致细胞活化相关表面marker表达增加，表达TH1型炎症因子。.3.发现颗粒物损伤树突状细胞的铁代谢相关机制。发现低浓度的颗粒物暴露可促进树突状细胞的成熟，而高浓度具有抑制效应；揭示了树突状细胞分化和成熟过程中铁相关基因的动态变化特征，发现环境中铁元素的紊乱可能直接影响树突状细胞的功能。