21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision-Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial-Induced Lung Fibrosis.

There is an urgent need for reliable toxicity assays to support the human health risk assessment of an ever increasing number of engineered nanomaterials (ENMs). Animal testing is not a suitable option for ENMs. Sensitive in vitro models and mechanism-based targeted in vitro assays that enable accurate prediction of in vivo responses are not yet available. In this proof-of-principle study, publicly available mouse lung transcriptomics data from studies investigating xenobiotic-induced lung diseases are used and a 17-gene biomarker panel (PFS17) applicable to the assessment of lung fibrosis is developed. The PFS17 is validated using a limited number of in vivo mouse lung transcriptomics datasets from studies investigating ENM-induced responses. In addition, an ex vivo precision-cut lung slice (PCLS) model is optimized for screening of potentially inflammogenic and pro-fibrotic ENMs. Using bleomycin and a multiwalled carbon nanotube, the practical application of the PCLS method as a sensitive alternative to whole animal tests to screen ENMs that may potentially induce inhalation toxicity is shown. Conditional to further optimization and validation, it is established that a combination of PFS17 and the ex vivo PCLS method will serve as a robust and sensitive approach to assess lung inflammation and fibrosis induced by ENMs.