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Transcriptomic characterization of C57BL/6 mouse embryonic stem cell differentiation and its modulation by developmental toxicants

ABSTRACT: To develop an in vitro model for developmental toxicity testing, we characterized gene expression changes during mouse embryonic stem cell (mESC) differentiation and their modulation by developmental toxicants. C57BL/6 mESCs were allowed to differentiate spontaneously and global gene expression changes were studied using microarrays at at different time points after embryoid body (EB) formation. Develpmental toxicants tested include 2.0 mM monobutyl phthalate (MBP), 0.25 mM thalidomide (THD), and 1.0 mM valproic acid (VPA).

ORGANISM(S): Mus musculus

PROVIDER: GSE60174 | GEO | 2014/09/09

SECONDARY ACCESSION(S): PRJNA257665

REPOSITORIES: GEO

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Transcriptomic characterization of C57BL/6 mouse embryonic stem cell differentiation and its modulation by developmental toxicants

Project description:To develop an in vitro model for developmental toxicity testing, we characterized gene expression changes during mouse embryonic stem cell (mESC) differentiation and their modulation by developmental toxicants. C57BL/6 mESCs were allowed to differentiate spontaneously and global gene expression changes were studied using microarrays at at different time points after embryoid body (EB) formation. Develpmental toxicants tested include 2.0 mM monobutyl phthalate (MBP), 0.25 mM thalidomide (THD), and 1.0 mM valproic acid (VPA). RNA of control samples (unexposed) was collected at 0, 24, 48, 72, 96, 120 and 168 h after EB formation; RNA of compound-exposed samples were collected at 24 h after EB formation. Three replicates were included for each experimental condition.

2014-09-09 | E-GEOD-60174 | biostudies-arrayexpress

Rat liver response to Clofibrate, DEHP or VPA

Project description:The project had 2 goals: 1) To evaluate the transcriptional response of 3 prototypical toxicants (Clofibrate, VPA, and DEHP) on rat lever. 2) To evaluate the impact pooling samples has on data analysis. Keywords = Clofibrate Keywords = Diethylhexyl phthalate Keywords = Phthalic acid bis(2-ethylhexyl ester) Keywords = Sodium Valproate Keywords = Valproic Acid Keywords = VPA Keywords = vehicle Keywords: other

2005-06-02 | GSE2303 | GEO

Thalidomide induced early gene expression perturbations indicative of human embryopathy in mouse embryonic stem cells

Project description:To unravel the mechanisms of thalidomide developmental toxicity, we used microarrays to study transcriptomic changes induced by thalidomide during mouse embryonic stem cell (mESC) differentiation. C57BL/6 mESCs were allowed to differentiate spontaneously and global gene expression changes were studied using microarrays at at different time points after exposure to 0.25 mM thalidomide (THD).

2015-05-31 | GSE61306 | GEO

human placenta-derived cell line (JEG-3): Control vs. valproic acid(VPA)-treated

Project description:Transcriptional profiling of human placenta-derived JEG-3 cell line comparing vehicle control with 7.38 mM of valproic acid(VPA)-treated JEG-3 cells for 48 hr. 7.38 mM valproic acid(VPA) induced the 30% inhibiotion of JEG-3 cell proliferation, G1 phase cell cycle arrest and the reduction of cell size. The Goal was to analyze the mechanism of valproic acid-induced adverse effects in placental cells.

2012-10-11 | GSE41441 | GEO

human placenta-derived cell line (JEG-3): Control vs. valproic acid(VPA)-treated

2012-10-11 | E-GEOD-41441 | biostudies-arrayexpress

Transcriptional changes of precision-cut liver slices after 3 days of cultures in the absence or presence of 2.5 mM valproic acid sodium salt.

Project description:Transcriptional changes of mouse precision-cut liver slices (PCLS) after three days of culture were determined using RNA sequencing. PCLS were cultured for three days in the absence or presence of 2.5 mM valproic acid sodium salt (VPA). Illumina NovaSeq SP was used for sequencing.

2022-04-20 | GSE194128 | GEO

A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation, and optimization for histone deacetylase inhibitors

Project description:Test systems to identify developmental toxicants are urgently needed. A combination of human stem cell technology and transcriptome analysis was used here to provide proof-of-concept that toxicants with a related mode of action can be identified, and grouped for read-across. We chose a test system of developmental toxicity, related to the generation of neuroectoderm from pluripotent stem cells (UKN1), and exposed cells for six days to benchmark concentration (BMC) of histone deacetylase inhibitors (HDACi) valproic acid, trichostatin-A, vorinostat, belinostat, panobinostat and entinostat. To provide insight into their toxic action, we identified HDACi consensus genes, assigned them to superordinate biological processes, and mapped them to a human transcription factor network constructed from hundreds of transcriptome data sets. We also tested a heterogeneous group of ‘mercurials’ (methylmercury, thimerosal, mercury(II)chloride, mercury(II)bromide, 4-chloromercuribenzoic acid, phenylmercuric acid) (BMCs). Microarray data were compared at the highest non-cytotoxic concentration for all 12 toxicants. A support vector machine (SVM)-based classifier predicted all HDACi correctly. For validation, the classifier was applied to legacy data sets of HDACi, and for each exposure situation, the SVM predictions correlated with the developmental toxicity. Finally, optimization of the classifier based on 100 probe sets showed that eight genes (F2RL2, TFAP2B, EDNRA, FOXD3, SIX3, MT1E, ETS1, LHX2) are sufficient to separate HDACi from mercurials. Our data demonstrate, how human stem cells and transcriptome analysis can be combined for mechanistic grouping and prediction of toxicants. Extension of this concept to mechanisms beyond HDACi would allow prediction of human developmental toxicity hazard of unknown compounds with the UKN1 test system.

2015-07-21 | GSE71127 | GEO

Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration

Project description:The in vitro test battery of the European research consortium ESNATS (‘novel stem cell-based test systems’) has been used to screen for potential human developmental toxicants. As part of this effort, the migration of neural crest (MINC) assay has been used to evaluate chemical effects on neural crest function. It identified some drug-like compounds in addition to known environmental toxicants. The hits included the HSP90 inhibitor geldanamycin, the chemotherapeutic arsenic trioxide, the flame-retardant PBDE-99, the pesticide triadimefon and the histone deacetylase inhibitors valproic acid and trichostatin A. Transcriptome changes triggered by these substances in human neural crest cells were recorded and analysed here to answer three questions: (1) can toxicants be individually identified based on their transcript profile; (2) how can the toxicity pattern reflected by transcript changes be compacted/ dimensionality-reduced for practical regulatory use; (3) how can a reduced set of biomarkers be selected for large-scale follow up? Transcript profiling allowed clear separation of different toxicants and the identification of toxicant types in a blinded test study. We also developed a diagrammatic system to visualize and compare toxicity patterns of a group of chemicals by giving a quantitative overview of altered superordinate biological processes (e.g. activation of KEGG pathways or overrepresentation of gene ontology terms). The transcript data were mined for potential markers of toxicity, and 39 transcripts were selected to either indicate general developmental toxicity or distinguish compounds with different modes-of-action in read-across. In summary, we found inclusion of transcriptome data to largely increase the information from the MINC phenotypic test.

2017-02-07 | GSE94521 | GEO

Protein data in PHH after VPA-treatment

Project description:LC-MS/MS protein data of Primary Human Hepatocytes (PHH) exposed to Valproic Acid (VPA) for 3 days daily and 3 days daily exposure followed by 3 days washout.

2018-02-27 | PXD007538 | Pride

Dysregulation of Wnt/β-Catenin Signaling pathway via RNF146 upregulation in the prefrontal cortex is responsible for social deficit in a VPA-induced ASD mouse model

Project description:Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder where patients have impaired social behavior, communication, repetitive behaviors, and restricted interest. Valproic acid (VPA) has been widely used to treat patients with epilepsy and bipolar disorder patients. However, VPA treatment during pregnancy has produced offspring with neurodevelopmental disorders, including ASD. To better understand the molecular function of ASD, we have used valproic acid, chemically induced ASD mice. We have performed LC-MS/MS analysis of VPA-induced offspring mice to the control to see the difference in their proteome difference. Our analysis showed that many neuronal network pathways were highly expressed in our differentially expressed proteins, and among them, Wnt/ β-catenin pathways showed clear enrichment. The RNF146 (E3 Ubiquitin-protein ligase) increase in VPA-exposed mice showed a highly significant effect on canonical Wnt/ β-catenin signaling pathways by disrupting the β-catenin destruction complex. The proteins like CREBBP, TCF4, and GSK3B also showed significant changes that indicate dysfunction of β-catenin destruction complex and activation of transcription factors.

2023-07-24 | PXD036413 | Pride

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