小尺寸石墨烯长期暴露后在小鼠体内的分布、迁移、转化和致毒机制研究

Rapid development and ever-increasing use of graphene will lead to heightened levels of this nanomaterial in the environment, thus increasing the potential exposure risks to human being. Synthesized graphene are varying substantially in size and the small sizes with better stability are popular for application. Particularly, the size of graphene is likely reduced by environmental transformation. However, the impact of size on its transport, transformation, and toxicity are largely unknown to date. The proposed study focus on the bioaccumulation, bio-distribution, metabolic products and toxic response of graphene in mice after a long exposure time. The relationship between the toxicity of graphene and its distribution/concentration in tissues will be established. The study will also explore the potential maternal transfer of the bio-accumulated graphene in mice and its toxic effects on the offspring. The object is to provide fundamental and systematic information regarding the environmental and exposure behaviors of graphene. This information will enable science-informed assessments of the environmental risks related to exposure of graphene in various scenarios. Such proactive assessments are critically needed by government and the science community to guide a safe development, production, distribution, and disposal of graphene nanomaterials.

石墨烯的高速发展和应用势必将导致其在环境中数量的急剧增长。人工合成的石墨烯往往具有很宽的尺寸范围，并且从材料学角度看，小尺寸石墨烯水分散性好、可操作性强，是近期材料开发应用的焦点；此外，环境中石墨烯的化学转化也会导致其尺寸变小。然而，目前关于石墨烯尺寸大小对其环境风险影响的相关研究甚少。基于石墨烯进入生物体内的界面传输以及体内分布、代谢过程和致毒机制等信息在其环境风险评价中的重要性，本项目以小尺寸石墨烯为研究对象，借助14C和13C标记技术，拟从组织、器官、细胞及亚细胞水平上充分认识不同暴露时期小尺寸石墨烯在小鼠体内的分布，进而研究其在生物体各组织的富集-排泄动力学、穿透生物屏障能力及进入细胞、在细胞中随时间转运和被细胞清除的机制，探讨石墨烯的“内暴露”剂量、存在形态与毒性效应间的内在联系，阐明微观致毒机制；揭示在小鼠体内石墨烯的子母代际传递规律，为石墨烯的环境风险评价提供关键科学基础。

石墨烯科技是当今世界研究和开发的热点，而研究石墨烯的生物安全性是石墨烯科技可持续发展的重大需求。但由于缺乏有效的定量、追踪的手段，使得石墨烯在生物体内各组织中的累积、转运和转化行为以及被细胞清除等过程和机制的定量研究十分匮乏。本项目在同位素标记石墨烯成功合成的基础上，首先定量研究了不同尺寸石墨烯在小鼠各组织器官、亚器官、细胞及亚细胞水平的分布规律，阐明了石墨烯进入小鼠体内的界面传输过程和机制，并进一步厘清了石墨烯尺寸对其在小鼠体内传输过程的影响；其次，探究了石墨烯在小鼠肝脏枯夫士细胞中的转化行为，揭示了石墨烯在血红素铁介导到类芬顿反应下的代谢路径。此外，探究了不同尺寸石墨烯对红细胞的溶血效应，揭示了基于溶血效应而导致的肝脏中铁平衡失稳机制。最后通过定量分析母代小鼠生殖系统以及子代小鼠体内的石墨烯含量，揭示了石墨烯在小鼠亲子代间的传递规律并进一步明确了石墨烯对子代小鼠生长发育的影响。研究结果将推动我国医用及工业应用石墨烯类材料安全评价方法与技术的建立。