Davidson Donna C, Derk Raymond, He Xiaoqing, Stueckle Todd A, Cohen Joel, Pirela Sandra V, Demokritou Philip, Rojanasakul Yon, Wang Liying
National Institute for Occupational Safety and Health, Health Effects Laboratory Division, 1095 Willowdale Road, Morgantown, WV, 26505, USA.
Department of Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, USA.
Part Fibre Toxicol. 2016 May 4;13(1):23. doi: 10.1186/s12989-016-0134-8.
Nano-scaled cerium oxide (nCeO2) is used in a variety of applications, including use as a fuel additive, catalyst, and polishing agent, yet potential adverse health effects associated with nCeO2 exposure remain incompletely understood. Given the increasing utility and demand for engineered nanomaterials (ENMs) such as nCeO2, "safety-by-design" approaches are currently being sought, meaning that the physicochemical properties (e.g., size and surface chemistry) of the ENMs are altered in an effort to maximize functionality while minimizing potential toxicity. In vivo studies have shown in a rat model that inhaled nCeO2 deposited deep in the lung and induced fibrosis. However, little is known about how the physicochemical properties of nCeO2, or the coating of the particles with a material such as amorphous silica (aSiO2), may affect the bio-activity of these particles. Thus, we hypothesized that the physicochemical properties of nCeO2 may explain its potential to induce fibrogenesis, and that a nano-thin aSiO2 coating on nCeO2 may counteract that effect.
Primary normal human lung fibroblasts were treated at occupationally relevant doses with nCeO2 that was either left uncoated or was coated with aSiO2 (amsCeO2). Subsequently, fibroblasts were analyzed for known hallmarks of fibrogenesis, including cell proliferation and collagen production, as well as the formation of fibroblastic nodules. The results of this study are consistent with this hypothesis, as we found that nCeO2 directly induced significant production of collagen I and increased cell proliferation in vitro, while amsCeO2 did not. Furthermore, treatment of fibroblasts with nCeO2, but not amsCeO2, significantly induced the formation of fibroblastic nodules, a clear indicator of fibrogenicity. Such in vitro data is consistent with recent in vivo observations using the same nCeO2 nanoparticles and relevant doses. This effect appeared to be mediated through TGFβ signaling since chemical inhibition of the TGFβ receptor abolished these responses.
These results indicate that differences in the physicochemical properties of nCeO2 may alter the fibrogenicity of this material, thus highlighting the potential benefits of "safety-by-design" strategies. In addition, this study provides an efficient in vitro method for testing the fibrogenicity of ENMs that strongly correlates with in vivo findings.
纳米级氧化铈（nCeO2）被用于多种应用，包括用作燃料添加剂、催化剂和抛光剂，但与接触nCeO2相关的潜在健康不良影响仍未完全了解。鉴于对诸如nCeO2等工程纳米材料（ENMs）的使用和需求不断增加，目前正在寻求“设计安全”方法，即改变ENMs的物理化学性质（例如尺寸和表面化学性质），以在最大限度地提高功能的同时尽量减少潜在毒性。体内研究在大鼠模型中已表明，吸入的nCeO2沉积在肺深部并诱发纤维化。然而，关于nCeO2的物理化学性质，或用诸如无定形二氧化硅（aSiO2）等材料对颗粒进行包被如何可能影响这些颗粒的生物活性，所知甚少。因此，我们推测nCeO2的物理化学性质可能解释其诱导纤维生成的潜力，并且在nCeO2上的纳米级aSiO2包被可能抵消该效应。
用未包被或用aSiO2包被（amsCeO2）的nCeO2以职业相关剂量处理原代正常人肺成纤维细胞。随后，分析成纤维细胞的纤维生成已知标志，包括细胞增殖和胶原蛋白产生，以及成纤维细胞结节形成。本研究结果与该假设一致，因为我们发现nCeO2在体外直接诱导I型胶原蛋白的大量产生并增加细胞增殖，而amsCeO2则不然。此外，用nCeO2而非amsCeO2处理成纤维细胞显著诱导成纤维细胞结节形成，这是纤维生成性的明确指标。此类体外数据与最近使用相同nCeO2纳米颗粒和相关剂量的体内观察结果一致。这种效应似乎是通过TGFβ信号传导介导的，因为对TGFβ受体的化学抑制消除了这些反应。
这些结果表明nCeO2物理化学性质的差异可能改变该材料的纤维生成性，从而突出了“设计安全”策略的潜在益处。此外，本研究提供了一种有效的体外方法来测试与体内研究结果密切相关的ENMs的纤维生成性。
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