Publication Details

Category Text Publication
Reference Category Journals
DOI 10.1093/gigascience/giz057
Licence creative commons licence
Title (Primary) Map and model—moving from observation to prediction in toxicogenomics
Author Schüttler, A.; Altenburger, R.; Ammar, M.; Bader-Blukott, M.; Jakobs, G.; Knapp, J.; Krüger, J.; Reiche, K.; Wu, G.-M.; Busch, W. ORCID logo
Source Titel GigaScience
Year 2019
Department BIOTOX; MOLSYB; DEVELOP
Volume 8
Issue 6
Page From giz057
Language englisch
Supplements https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/gigascience/8/6/10.1093_gigascience_giz057/1/giz057_supplementary_figures.pdf?Expires=1586865897&Signature=x8WWbwz5QRDJCnaata2lS8uuKOan397mNi39H5jXGN1ph1HE8LU2H2VzgmBQhg0LlWTHK6eCt6n2GMlv-aE~AAm5~AY4hN9RQwhXWAbNfmt86~SrcgFzjwfVd5QBNo99KZQhn8qC-hzCn2EJzUmdj4x109XpLhd2bdPd3-HHo2IgzP7lN2x7BWenCa7EP29mgugp4yY8dSvD7QzSlbXNGq5bo1h5gt0EsBKOE1qggcVw1dWQxaOcVaQLK3ORUpXGvltpSC0BVx2rg8oljM-TMQnartVOPPnMVwSmOn-eU62e4v8SwsmdpWyEHHij4TREUXcat5NJ40SYiptKVZ4q9A__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA
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Keywords risk assessment; environmental monitoring; adverse outcome pathway; mode of action; ’omics time course; dose response; machine learning; diuron; diclofenac; naproxen
Abstract

Background

Chemicals induce compound-specific changes in the transcriptome of an organism (toxicogenomic fingerprints). This provides potential insights about the cellular or physiological responses to chemical exposure and adverse effects, which is needed in assessment of chemical-related hazards or environmental health. In this regard, comparison or connection of different experiments becomes important when interpreting toxicogenomic experiments. Owing to lack of capturing response dynamics, comparability is often limited. In this study, we aim to overcome these constraints.

Results

We developed an experimental design and bioinformatic analysis strategy to infer time- and concentration-resolved toxicogenomic fingerprints. We projected the fingerprints to a universal coordinate system (toxicogenomic universe) based on a self-organizing map of toxicogenomic data retrieved from public databases. Genes clustering together in regions of the map indicate functional relation due to co-expression under chemical exposure. To allow for quantitative description and extrapolation of the gene expression responses we developed a time- and concentration-dependent regression model. We applied the analysis strategy in a microarray case study exposing zebrafish embryos to 3 selected model compounds including 2 cyclooxygenase inhibitors. After identification of key responses in the transcriptome we could compare and characterize their association to developmental, toxicokinetic, and toxicodynamic processes using the parameter estimates for affected gene clusters. Furthermore, we discuss an association of toxicogenomic effects with measured internal concentrations.

Conclusions

The design and analysis pipeline described here could serve as a blueprint for creating comparable toxicogenomic fingerprints of chemicals. It integrates, aggregates, and models time- and concentration-resolved toxicogenomic data.

Persistent UFZ Identifier https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=21907
Schüttler, A., Altenburger, R., Ammar, M., Bader-Blukott, M., Jakobs, G., Knapp, J., Krüger, J., Reiche, K., Wu, G.-M., Busch, W. (2019):
Map and model—moving from observation to prediction in toxicogenomics
GigaScience 8 (6), giz057