Inter-laboratory study of human in vitro toxicogenomics-based tests as alternative methods for evaluating chemical carcinogenicity: a bioinformatics perspective

The assessment of the carcinogenic potential of chemicals with alternative, human-based in vitro systems has become a major goal of toxicogenomics. The central read-out of these assays is the transcriptome, and while many studies exist that explored the gene expression responses of such systems, rep...

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Bibliographic Details
Published in:Archives of toxicology 2016-09, Vol.90 (9), p.2215-2229
Main Authors: Herwig, R., Gmuender, H., Corvi, R., Bloch, K. M., Brandenburg, A., Castell, J., Ceelen, L., Chesne, C., Doktorova, T. Y., Jennen, D., Jennings, P., Limonciel, A., Lock, E. A., McMorrow, T., Phrakonkham, P., Radford, R., Slattery, C., Stierum, R., Vilardell, M., Wittenberger, T., Yildirimman, R., Ryan, M., Rogiers, V., Kleinjans, J.
Format: Article
Language:English
Subjects:
Bioassays
Bioinformatics
Biomedical and Life Sciences
Biomedicine
Cancer
Carcinogens - classification
Carcinogens - toxicity
Cell Line, Tumor
Computational Biology
Dose-Response Relationship, Drug
Environmental Health
Gene Expression Profiling
Gene Expression Regulation - drug effects
Genome-Wide Association Study
Genomes
Humans
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - metabolism
Laboratory Proficiency Testing
Liver - drug effects
Liver - metabolism
Observer Variation
Occupational Medicine/Industrial Medicine
Oligonucleotide Array Sequence Analysis
Pharmacology/Toxicology
Reproducibility of Results
Risk Assessment
Time Factors
Toxicity
Toxicogenetics - methods
Toxicogenomics
Transcriptome - drug effects
Workflow
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Summary:The assessment of the carcinogenic potential of chemicals with alternative, human-based in vitro systems has become a major goal of toxicogenomics. The central read-out of these assays is the transcriptome, and while many studies exist that explored the gene expression responses of such systems, reports on robustness and reproducibility, when testing them independently in different laboratories, are still uncommon. Furthermore, there is limited knowledge about variability induced by the data analysis protocols. We have conducted an inter-laboratory study for testing chemical carcinogenicity evaluating two human in vitro assays: hepatoma-derived cells and hTERT-immortalized renal proximal tubule epithelial cells, representing liver and kidney as major target organs. Cellular systems were initially challenged with thirty compounds, genome-wide gene expression was measured with microarrays, and hazard classifiers were built from this training set. Subsequently, each system was independently established in three different laboratories, and gene expression measurements were conducted using anonymized compounds. Data analysis was performed independently by two separate groups applying different protocols for the assessment of inter-laboratory reproducibility and for the prediction of carcinogenic hazard. As a result, both workflows came to very similar conclusions with respect to (1) identification of experimental outliers, (2) overall assessment of robustness and inter-laboratory reproducibility and (3) re-classification of the unknown compounds to the respective toxicity classes. In summary, the developed bioinformatics workflows deliver accurate measures for inter-laboratory comparison studies, and the study can be used as guidance for validation of future carcinogenicity assays in order to implement testing of human in vitro alternatives to animal testing.
ISSN:0340-5761
1432-0738
DOI:10.1007/s00204-015-1617-3