21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision-Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial-Induced Lung Fibrosis
- DOI
- Language of the publication
- English
- Date
- 2020-04-29
- Type
- Article
- Author(s)
- Rahman, Luna
- Williams, Andrew
- Gelda, Krishna
- Nikota, Jake
- Wu, Dongmei
- Vogel, Ulla
- Halappanavar, Sabina
- Publisher
- Wiley
Abstract
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.
Plain language summary
Health Canada (HC) conducts research to determine the best approaches to investigate the toxicological hazards posed to humans by exposure to chemicals including emerging toxicants such as nanomaterials. Nanomaterials are a novel class of materials that are small (nano = one billionth of a meter). Conventional toxicity testing has always relied on animal testing, which is not a feasible option for the safety assessment of nanomaterials because 1) animal testing is time and resource intensive and 2) the sheer number of nanomaterials that require toxicity testing. The 21st century reform in toxicology advocates for non-animal methods or strategies that reduce animal use in substance-induced toxicity testing. However, scientifically validated animal alternatives and the guidance for using the toxicology data generated by such alternatives in decision making are not available. In the present study, using publicly available transcriptomics (genome-wide changes in expression of genes) data from mouse lungs exposed to different disease causing agents, a panel of 17-genes reflective of lung fibrosis disease was established. Lung fibrosis is characterised by scarring of lung tissue leading to reduced lung volume and difficulties in breathing. The 17-gene panel was tested for its predictive potential using other publicly available transcriptomics data from lungs of mice exposed to nanomaterials known to induce the fibrotic disease. In addition, a live lung tissue slice culturing method that significantly reduces the number of animals used in a standard toxicity testing, was optimised. Conditional to further optimisation and validation, the study establishes that a combination of the 17-gene panel and lung slice culture method will serve as a robust and sensitive approach in assessing lung toxicity induced by nanomaterials. This publication is an invited contribution to a special edition of Small (https://onlinelibrary.wiley.com/journal/16136829) on ‘Rethinking Nanosafety’.
Subject
- Health,
- Health and safety