Application of omics data in regulatory toxicology: report of an international BfR expert workshop

Marx‐Stoelting, Philip; Braeuning, Albert; Buhrke, Thorsten; Lampen, Alfonso; Niemann, Lars; Oelgeschlaeger, Michael; Rieke, S.; Schmidt, Folke; Heise, T.; Pfeil, R.; Solecki, Roland

doi:10.1007/s00204-015-1602-x

Cited by 32 publications

(24 citation statements)

References 15 publications

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“…Technologies measuring the entirety of gene transcripts, proteins or metabolites in a sample (“omics”) are increasingly used in toxicological research and are discussed to be included into chemical regulatory assessments in the future (Marx-Stoelting et al , 2015). In toxicology, these methods are primarily used to obtain insight into a compound’s mode of action, to group similarly acting compounds or to define new biomarkers (Afshari et al , 2011).…”

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confidence: 99%

The Transcriptome of the Zebrafish Embryo After Chemical Exposure: A Meta-Analysis

Schüttler

Reiche

Altenburger

et al. 2017

Toxicological Sciences

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Numerous studies have been published in the past years investigating the transcriptome of the zebrafish embryo (ZFE) upon being subjected to chemical stress. Aiming at a more mechanistic understanding of the results of such studies, knowledge about commonalities of transcript regulation in response to chemical stress is needed. Thus, our goal in this study was to identify and interpret genes and gene sets constituting a general response to chemical exposure. Therefore, we aggregated and reanalyzed published toxicogenomics data obtained with the ZFE. We found that overlap of differentially transcribed genes in response to chemical stress across independent studies is generally low and the most commonly differentially transcribed genes appear in less than 50% of all treatments across studies. However, effect size analysis revealed several genes showing a common trend of differential expression, among which genes related to calcium homeostasis emerged as key, especially in exposure settings up to 24 h post-fertilization. Additionally, we found that these and other downregulated genes are often linked to anatomical regions developing during the respective exposure period. Genes showing a trend of increased expression were, among others, linked to signaling pathways (e.g., Wnt, Fgf) as well as lysosomal structures and apoptosis. The findings of this study help to increase the understanding of chemical stress responses in the developing zebrafish embryo and provide a starting point to improve experimental designs for this model system. In future, improved time- and concentration-resolved experiments should offer better understanding of stress response patterns and access to mechanistic information.

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confidence: 99%

The Transcriptome of the Zebrafish Embryo After Chemical Exposure: A Meta-Analysis

Schüttler

Reiche

Altenburger

et al. 2017

Toxicological Sciences

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“…At present, a practical application of the Tox21c vision is still far away because of the limited confidence in the new method as the causal link between in vitro data, obtained with new technologies, and adverse effects, tested in vivo , is difficult to establish. The crucial confidence can be reached by simultaneously evaluating phenotypic and molecular endpoints, the latter achievable through in vitro Omics analyses34, considering that the chemical-cell/organ interaction in vivo can be characterized by compensation and adaptive response not necessarily developed in differentiated cell cultures.…”

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confidence: 99%

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Porreca

D’Angelo

Franceschi

et al. 2016

Sci Rep

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In vitro Omics analysis (i.e. transcriptome) is suggested to predict in vivo toxicity and adverse effects in humans, although the causal link between high-throughput data and effects in vivo is not easily established. Indeed, the chemical-organism interaction can involve processes, such as adaptation, not established in cell cultures. Starting from this consideration we investigate the transcriptomic response of immortalized thyrocytes to ethylenthiourea and chlorpyrifos. In vitro data revealed specific and common genes/mechanisms of toxicity, controlling the proliferation/survival of the thyrocytes and unrelated hematopoietic cell lineages. These results were phenotypically confirmed in vivo by the reduction of circulating T4 hormone and the development of pancytopenia after long exposure. Our data imply that in vitro toxicogenomics is a powerful tool in predicting adverse effects in vivo, experimentally confirming the vision described as Tox21c (Toxicity Testing in the 21st century) although not fully recapitulating the biocomplexity of a living animal.

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“…This is especially related to a lack of method harmonization, standardization and validation of experimental design and data evaluation; in addition, the current definition of adversity of compound‐induced effects impedes the use of omics data in toxicology. Results of a recent workshop on the use of omics technologies in regulatory science have shown that most experts favor an increasing application of omics techniques in toxicological testing in the future, but still feel that additional steps are necessary prior to routine implementation of omics technologies in regulatory test batteries (Marx‐Stoelting et al, ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic effect marker patterns of genotoxins – a comparative study with literature data

Kreuzer

Frenzel

Lampen

et al. 2019

J of Applied Toxicology

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Microarray approaches are frequently used experimental tools which have proven their value for example in the characterization of the molecular mode of action of toxicologically relevant compounds. In a regulatory context, omics techniques are still not routinely used, amongst others due to lacking standardization in experimental setup and data processing, and also due to issues with the definition of adversity. In order to exemplarily determine whether consensus transcript biomarker signatures for a certain toxicological endpoint can be derived from published microarray datasets, we here compared transcriptome data from human HepaRG hepatocarcinoma cells treated with different genotoxins, based on re‐analyzed datasets extracted from the literature. Comparison of the resulting data show that even with similarly‐acting compounds in the same cell line, considerable variation was observed with respect to the numbers and identities of differentially expressed genes. Greater concordance was observed when considering the whole data sets and biological functions associated with the genes affected. The present results highlight difficulties and possibilities in inter‐experiment comparisons of omics data and underpin the need for future efforts towards improved standardization to facilitate the use of omics data in risk assessment. Existing omics datasets may nonetheless prove valuable in establishing biological context information essential for the development of adverse outcome pathways.

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Application of omics data in regulatory toxicology: report of an international BfR expert workshop

Cited by 32 publications

References 15 publications

The Transcriptome of the Zebrafish Embryo After Chemical Exposure: A Meta-Analysis

The Transcriptome of the Zebrafish Embryo After Chemical Exposure: A Meta-Analysis

Pesticide toxicogenomics across scales: in vitro transcriptome predicts mechanisms and outcomes of exposure in vivo

Transcriptomic effect marker patterns of genotoxins – a comparative study with literature data

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