The effect of zirconium doping of cerium dioxide nanoparticles on pulmonary and cardiovascular toxicity and biodistribution in mice after inhalation

Development and manufacture of nanomaterials is growing at an exponential rate, despite an incomplete understanding of how their physicochemical characteristics affect their potential toxicity. Redox activity has been suggested to be an important physicochemical property of nanomaterials to predict their biological activity. This study assessed the influence of redox activity by modification of cerium dioxide nanoparticles (CeO2 NPs) via zirconium (Zr) doping on the biodistribution, pulmonary and cardiovascular effects in mice following inhalation. Healthy mice (C57BL/6 J), mice prone to cardiovascular disease (ApoE−/−, western-diet fed) and a mouse model of neurological disease (5 × FAD) were exposed via nose-only inhalation to CeO2 NPs with varying amounts of Zr-doping (0%, 27% or 78% Zr), or clean air, over a four-week period (4 mg/m3 for 3 h/day, 5 days/week). Effects were assessed four weeks post-exposure. In all three mouse models CeO2 NP exposure had no major toxicological effects apart from some modest inflammatory histopathology in the lung, which was not related to the amount of Zr-doping. In ApoE−/− mice CeO2 did not change the size of atherosclerotic plaques, but there was a trend towards increased inflammatory cell content in relation to the Zr content of the CeO2 NPs. These findings show that subacute inhalation of CeO2 NPs causes minimal pulmonary and cardiovascular effect four weeks post-exposure and that Zr-doping of CeO2 NPs has limited effect on these responses. Further studies with nanomaterials with a higher inherent toxicity or a broader range of redox activities are needed to fully assess the influence of redox activity on the toxicity of nanomaterials.尽管目前对纳米材料的理化特性（physicochemical characteristics）如何影响其潜在毒性的认知仍不全面，但纳米材料的开发与制造正以指数级速率快速发展。有研究指出，氧化还原活性（redox activity）可作为预测纳米材料生物活性的关键理化属性。本研究通过锆（Zr）掺杂修饰二氧化铈纳米颗粒（CeO₂ NPs），以此调控其氧化还原活性，探究该修饰后的纳米颗粒经吸入暴露后对小鼠的生物分布（biodistribution）、肺部与心血管效应的影响。本研究选用三类小鼠模型：健康C57BL/6 J小鼠、饲以西式饮食的载脂蛋白E敲除（ApoE−/−）心血管疾病易感小鼠，以及5×FAD神经疾病模型小鼠。采用仅鼻吸入暴露（nose-only inhalation）方式，使小鼠分别暴露于不同锆掺杂比例（0%、27%或78% Zr）的CeO₂ NPs环境，或清洁空气，暴露周期为四周（每日3小时，每周5天，暴露浓度为4 mg/m³），并于暴露结束后四周开展效应评估。实验结果显示，在三类小鼠模型中，CeO₂ NP暴露均未引发显著毒理学效应，仅在肺部观察到轻度炎症性组织病理学（inflammatory histopathology）改变，且该改变与锆掺杂比例无相关性。在ApoE−/−小鼠中，CeO₂ NP暴露未改变动脉粥样硬化斑块（atherosclerotic plaques）的大小，但随着CeO₂ NPs中锆掺杂量的升高，斑块内炎症细胞含量呈现上升趋势。本研究结果表明，亚急性吸入暴露CeO₂ NPs后，小鼠在暴露后四周仅表现出极轻微的肺部与心血管效应，且锆掺杂对CeO₂ NPs的上述毒性响应影响有限。未来仍需采用固有毒性更高、氧化还原活性范围更广的纳米材料开展进一步研究，以全面评估氧化还原活性对纳米材料毒性的影响。