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Background  Nano-scaled cerium oxide (nCeO 2 ) is used in a variety of applications, including use as a fuel additive, catalyst, and polishing agent, yet potential adverse health effects associated with nCeO 2  exposure remain incompletely understood. Given the increasing utility and demand for engineered nanomaterials (ENMs) such as nCeO 2 , “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 nCeO 2  deposited deep in the lung and induced fibrosis. However, little is known about how the physicochemical properties of nCeO 2,  or the coating of the particles with a material such as amorphous silica (aSiO 2 ), may affect the bio-activity of these particles. Thus, we hypothesized that the physicochemical properties of nCeO 2  may explain its potential to induce fibrogenesis, and that a nano-thin aSiO 2  coating on nCeO 2  may counteract that effect.    Results  Primary normal human lung fibroblasts were treated at occupationally relevant doses with nCeO 2  that was either left uncoated or was coated with aSiO 2  (amsCeO 2 ). 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 nCeO 2  directly induced significant production of collagen I and increased cell proliferation  in vitro , while amsCeO 2  did not. Furthermore, treatment of fibroblasts with nCeO 2 , but not amsCeO 2 , 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 nCeO 2  nanoparticles and relevant doses. This effect appeared to be mediated through TGFβ signaling since chemical inhibition of the TGFβ receptor abolished these responses.    Conclusions  These results indicate that differences in the physicochemical properties of nCeO 2  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.

Direct stimulation of human fibroblasts by nCeO2 in vitro is attenuated with an amorphous silica coating