E-MTAB-2080 - A Systems Biology Approach For Evaluating The Biological Impact Of Environmental Toxicants In Vitro
Submitted on 1 May 2010, last updated on 6 May 2014, released on 9 May 2014
Exposure to cigarette smoke is a leading cause of lung diseases including chronic obstructive pulmonary disease and cancer. Cigarette smoke is a complex aerosol containing over 6000 chemicals, and thus it is difficult to determine individual contributions to overall toxicity, and the molecular mechanisms by which smoke constituents exert their effects. We selected three well-known harmful and potentially harmful constituents (HPHCs) in tobacco smoke: acrolein, formaldehyde and catechol and established a High Content Screening (HCS) method using normal human bronchial epithelial cells, which are the first bronchial cells in contact with cigarette smoke. The impact of each HPHC was investigated using 13 multi-parametric indicators of cellular toxicity and complemented with a microarray-based whole transcriptome analysis followed by a computational approach leveraging mechanistic network models to identify and quantify perturbed molecular pathways. HPHCs were evaluated over a wide range of concentrations and at different exposure time points (4 h, 8 h, and 24 h). By High Content Screening, the toxic effects of the three HPHCs could only be observed at the highest doses. Whole genome transcriptomics unraveled toxicity mechanisms at lower doses and earlier time points. The most prevalent toxicity mechanisms observed were: DNA damage/growth arrest, oxidative stress, mitochondrial stress and apoptosis/necrosis. In summary, combination of multiple toxicological endpoints with a systems-based impact assessment allows for a more robust scientific basis for the toxicological assessment of HPHCs that allows insight into time- and dose-dependent molecular perturbations of specific biological pathways. This approach allowed us to establish an in vitro Systems Toxicology platform that can be applied to a broader selection of HPHCs and their mixtures and can serve more generally as the basis for testing the impact of other environmental toxicants on normal bronchial epithelial cells.
transcription profiling by array, compound treatment design, dose response, in vitro, time series
A Systems Biology Approach For Evaluating The Biological Impact Of Environmental Toxicants In Vitro. Ignacio Gonzalez-Suarez; Alain Sewer; Paul Walker; Carole Mathis; Samantha Ellis; Heather Woodhouse; Emmanuel Guedj; Remi Dulize; Diego Marescotti; Stefano Acali; Florian Martin; Nikolai Ivanov; Julia Hoeng; Manuel C. Peitsch.