低剂量纳米银的红系发育毒性及分子机制研究

Silver nanoparticles are one of the most widely used nanomaterials in health care and daily life, which are also one of the most environmental health risky nanomaterials. Though the toxicity of silver nanoparticles has been widely studied, previous research on the toxicity features and related mechanisms of silver nanoparticles are usually based on the high dose of silver nanoparticles exposure. However, the knowledge of toxicity and health risk of low dose of silver nanoparticles in environment is still largely unknown. For example, whether low dose of silver nanoparticles could induce blood toxicity was rarely studied. Our previous results showed that low dose of silver nanoparticles could obviously inhibit erythroid cells development. Therefore, on this basis, this project will focus on the toxicity of low dose of silver nanoparticle on erythroid cells development and reveal related mechanism: (1) Dose, shape and nanoparticle/ion dependent silver nanoparticles-induced inhibitory effect on erythroid precursor cells differentiation;(2) The effect of physical and chemical properties of silver nanoparticles on the membrane skeleton protein and blood oxygen saturation of red cells; (3) Erythroid differentiation related transcriptional factors, signal pathways and epigenetic modification-mediated silver nanoparticles induced erythroid cells development toxicity. Thus this project will provide theoretical basis and scientific guidance for the biological safety and environmental health risky of silver nanoparticles.

纳米银是医疗卫生和日常生活等领域应用最广泛，也是目前环境健康风险最高的人工纳米材料之一。尽管针对纳米银的毒性已开展了大量研究，但以往的研究往往基于高剂量暴露下获得的毒性特征和机制。然而,目前对于纳米银在环境低剂量暴露下的毒性与健康危害认识较少，例如，低剂量暴露下纳米银是否诱发血液毒性，仍不清楚。本研究组前期的研究结果表明，在一系列金属纳米材料中，低剂量纳米银可产生明显的红系细胞发育障碍的效应。在此基础上，本项目将深入探讨低剂量纳米银暴露对红系发育的毒性效应和机理：（1）纳米银暴露诱导红系前体细胞分化抑制的剂量-效应关系、形貌-效应关系和颗粒/离子-效应关系；（2）纳米银的理化特征对成熟红细胞膜骨架蛋白和血氧饱和度的影响；（3）纳米银暴露下红系分化相关转录因子、重要信号通路和表观修饰调控改变所介导的红系发育毒性机制研究。本项目的开展将为评价纳米银的生物安全性和环境健康风险提供科学依据。

纳米银是日常生产生活中应用最为广泛的纳米材料之一，近些年来它的生物安全性和健康危害效应也受到人们越来越多的重视。纳米银主要通过诱发细胞氧化损伤和脂质过氧化，炎症因子释放及细胞凋亡通路活化等途径造成细胞毒性，但纳米银是否通过影响胞内表观遗传调控特别是长链非编码RNA（LncRNA）的表达诱发细胞损伤效应仍不明确，并亟待进一步的研究。本项目通过研究纳米银对红系前体细胞的毒性效应，探讨了lncRNAs在此过程中的生物学功能并进行了深入的分子机制探讨。本项目研究发现纳米银暴露下lncRNA ODRUL的表达显著增加并促进了纳米银诱发的红系细胞毒性效应。纳米银能导致胞内ROS生成以及氧化应激分子Nrf2的表达增加，继而导致ODRUL的转录表达上调。另外通过RNA-pull down等实验，我们鉴定出PI4K激酶是ODRUL的相互作用蛋白。ODRUL能够结合并抑制PI4Ka的激酶活性，从而导致后者下游细胞生存分子AKT的活性受到抑制以及细胞凋亡分子JNK的活性上调，最终协同抑制细胞生存调节分子Bcl-2的表达水平并促进红系细胞走向死亡。我们的结果发现长链非编码RNA ODRUL是新的纳米银红系细胞毒性调控分子，为纳米银的生物安全性评价提供新的研究思路和重要的理论基础，并为纳米银的细胞毒性提供新的预防策略。