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Design Principles of Concentration-Dependent Transcriptome Deviations in Drug-Exposed Differentiating Stem Cells
Open accessAbstract
Information on design principles governing transcriptome changes upon transition from safe to hazardous drug concentrations or from tolerated to cytotoxic drug levels are important for the application of toxicogenomics data in developmental toxicology. Here, we tested the effect of eight concentrations of valproic acid (VPA; 25-1000 μM) in an assay that recapitulates the development of human embryonic stem cells to neuroectoderm. Cells were exposed to the drug during the entire differentiation process, and the number of differentially regulated genes increased continuously over the concentration range from zero to about 3000. We identified overrepresented transcription factor binding sites (TFBS) as well as superordinate cell biological processes, and we developed a gene ontology (GO) activation profiler, as well as a two-dimensional teratogenicity index. Analysis of the transcriptome data set by the above biostatistical and systems biology approaches yielded the following insights: (i) tolerated (≤25 μM), deregulated/teratogenic (150-550 μM), and cytotoxic (≥800 μM) concentrations could be differentiated. (ii) Biological signatures related to the mode of action of VPA, such as protein acetylation, developmental changes, and cell migration, emerged from the teratogenic concentrations range. (iii) Cytotoxicity was not accompanied by signatures of newly emerging canonical cell death/stress indicators, but by catabolism and decreased expression of cell cycle associated genes. (iv) Most, but not all of the GO groups and TFBS seen at the highest concentrations were already overrepresented at 350-450 μM. (v) The teratogenicity index reflected this behavior, and thus differed strongly from cytotoxicity. Our findings suggest the use of the highest noncytotoxic drug concentration for gene array toxicogenomics studies, as higher concentrations possibly yield wrong information on the mode of action, and lower drug levels result in decreased gene expression changes and thus a reduced power of the study.
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Although cytotoxicity measures are fundamental in assessing a drug's potential for hepatotoxicity in vitro, gene expression and various phenotypic changes can occur at much lower concentrations.
“although cytotoxicity measures are fundamental in the assessment of a drug’s potential for hepatotoxicity in vitro33,34, gene expression and various phenotypic changes can occur at much lower concentrations35,36.”
From Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology (2022) · cites this paper as [36]
The Discussion reports altered gene expression and functional-process signatures at 350 μM VPA, below the 800 μM threshold for cytotoxicity. The paper studies differentiating stem cells and infers developmental disturbances from transcriptomic analyses; it does not establish that various measured phenotypic changes occur at those lower concentrations. The hepatotoxicity clause has separate citations and is not attributed to this source. (LLM, conf=0.85)
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Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology
Ewart, L., Apostolou, A., Briggs, S. A., Carman, C. V., Chaff, J. T., Heng, A. R., Jadalannagari, S., Janardhanan, J., Jang, K.-J., Joshipura, S. R., et al. (2022) · Communications Medicine · doi:10.1038/s43856-022-00209-1 · Cited by 337
Metadata
- Authors
- Waldmann, T., Rempel, E., Balmer, N. V., König, A., Kolde, R., Gaspar, J. A., Henry, M., Hescheler, J., Sachinidis, A., Rahnenführer, J., Hengstler, J. G., & Leist, M.
- Affiliations
- University of Konstanz (DE)
- TU Dortmund University (DE)
- Quretec (Estonia) (EE)
- University of Cologne (DE)
- Corresponding author
- Waldmann, Tanja
- ORCID
- Venue
- Chemical Research in Toxicology
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-01-21
- Volume
- 27
- Issue
- 3
- Pages
- 408-420
- ISSN
- 0893-228X (ISSN-L)
- 1520-5010
- PMC
- PMC3958134
- OpenAlex
- W2085421312
- Cited by
- 106
- References
- 3
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 1 · 2022: 7 · 2021: 7 · 2020: 12 · 2019: 8 · 2018: 12 · 2017: 8 · 2016: 12 · 2015: 17 · 2014: 18
- FWCI
- 17.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Chemical Research in Toxicology (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- valproic acid, developmental toxicity, transcriptome, human embryonic stem cells, neuroectoderm differentiation, cytotoxicity, transcription factor binding sites, mechanism of action, protein acetylation, cell migration, cell cycle genes, drug concentration dependence, toxicogenomics
- MeSH terms
- Binding Sites, Cell Differentiation, Cells, Cultured, Humans, Transcription Factors, Valproic Acid, Down-Regulation, Up-Regulation, Cluster Analysis, Principal Component Analysis, Embryonic Stem Cells, Neural Plate, Transcriptome
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