Abstract
The immense diversity and constant development of nanomaterials (NMs) increase the need for a facilitated risk assessment, which requires knowledge of the modes of action (MoAs) of NMs. This necessitates a comprehensive data basis, which can be obtained using omics. Furthermore, the establishment of suitable in vitro test systems is essential to follow the 3R concept and to cope with the high number of NMs.In the present study, we aimed to compare NM effects in vitro and in vivo using a multi-omics approach. We applied an integrated data analysis strategy based on proteomics and metabolomics to four silica NMs and one titanium dioxide-based NM. For the in vitro investigations, rat alveolar epithelial cells (RLE-6TN) and rat alveolar macrophages (NR8383) were treated with different doses of NMs, and the results were compared with the effects on rat lungs after short-term inhalations and instillations.Since reactive oxygen species (ROS) production has been described as a critical biological effect of NMs, we focused on different levels of oxidative stress. Thus, we found opposite changes in proteins and metabolites related to the production of reduced glutathione in alveolar epithelial cells and alveolar macrophages, demonstrating that the MoAs of NMs depend on the model system used. Interestingly, in vivo, pathways related to inflammation were more affected than oxidative stress responses. Hence, the assignment of the observed effects to levels of oxidative stress was also different in vitro and in vivo.However, the overall classification of “active” and “passive” NMs was consistent in vitro and in vivo, suggesting that both cell lines tested are suitable for the assessment of NM toxicity. In summary, the results presented here highlight the need to carefully review model systems to decipher the extent to which they can replace in vivo assays.
Highlights
The immense variety and constant development of nanomaterials (NMs) raise the demand for a facilitated risk assessment, for which knowledge on NMs mode of actions (MoAs) is required
The consistent classification indicates both tested cell lines to be suitable for NM toxicity assessment even though the induced levels of oxidative stress strongly depend on the used model systems
The here presented results highlight that model systems need to be carefully revised to decipher the extent to which they can replace in vivo testing
Summary
The immense variety and constant development of nanomaterials (NMs) raise the demand for a facilitated risk assessment, for which knowledge on NMs mode of actions (MoAs) is required. For this purpose, a comprehensive data basis is of paramountcy that can be obtained using omics. New NM variants are continuously developed and previous studies have shown that especially silica or titanium dioxide NMs are among those with the highest production volumes of 5,500 – 2400,000 t and 3,000 – 88,000 t worldwide per year, respectively [2, 3, 4, 5] This makes a detailed characterization of their possible health effects indispensable. We focused on NMs MoAs in vitro and in vivo and on the transferability of both approaches
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