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GSE84250
Homo sapiens
12 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2), (imblegenhumandnamethylation2.1mdeluxepromoterarray[100929hg19deluxeprommethhx1)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Valproic acid (VPA) is a very potent anti-cancer and neuro-protective drug. However, exposure to VPA may cause accumulation of lipids in the liver which could result in the development of steatosis. As VPA is a fatty acid analogue, most of the performed studies focus on inhibition of the mitochondrial b-oxidation pathway as the possible mode of action. However, investigations exploring the contribution of other processes in particular by using whole genome studies in a relevant human liver model are limited. Furthermore, the contribution of gene expression regulation by DNA methylation changes and/or miRNA changes is hardly known. Therefore, in the present study, we investigated the effect of repetitive VPA exposure on primary human hepatocytes (PHH) on whole genome gene expression-, DNA methylation-, and miRNA changes, using microarrays and integrated data analyses. PHH were exposed to a non-cytotoxic dose of 15 mM VPA for 5 days daily thereby inducing accumulation of lipids. Part of the PHH was left untreated for an additional 3 days in order to study the persistence of changes. VPA modulated the expression of a number of nuclear receptors and their target genes, leading to disturbed fatty acid metabolism and - uptake, ultimately leading to accumulation of triglycerides in the liver which is the key event leading to steatosis. Part of the gene expression changes was epigenetically regulated. Furthermore, after terminating the treatment, the expression and DNA methylation changes of several genes remained persistent, indicating a permanent change in the PHH, causing steatosis development to continue and/or making the PHH more sensitive for steatosis development during a subsequent exposure.
Publication Title
Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 124 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
The transcriptomic changes induced in the human liver cell line HepG2 by 100M menadione, 200M TBH or 50M H2O2 after treatment for 0.5, 1, 2, 4, 6, 8 and 24h.
Publication Title
Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 560 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The lack of accurate in vitro assays for predicting in vivo toxicity of chemicals together with new legislations demanding replacement and reduction of animal testing has triggered the development of alternative methods. This study aimed at developing a transcriptomics-based in vitro prediction assay for in vivo genotoxicity. The transcriptomics changes induced in the human liver cell line HepG2 by 34 compounds after treatment for 12h, 24h and 48h were used for the selection of gene-sets that can discriminate between in vivo genotoxins (GTX) and in vivo non-genotoxins (NGTX). By combining publicly available results for these chemicals from standard in vitro genotoxicity studies with transcriptomics, we developed several prediction models. These models were validated by means of an additional set of 28 chemicals.
Publication Title
A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo.
Sample Metadata Fields
Cell line, Time
View Samples- Mus musculus
- 177 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302), miRCURY LNA microRNA Array, 5th and 7th generation combined - hsa, mmu & rno (miRBase 19.0)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Exploiting microRNA and mRNA profiles generated in vitro from carcinogen-exposed primary mouse hepatocytes for predicting in vivo genotoxicity and carcinogenicity.
Sample Metadata Fields
Specimen part, Compound
View Samples- Mus musculus
- 177 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The well-defined battery of in vitro systems applied within chemical cancer risk assessment is often characterised by a high false-positive rate, thus repeatedly failing to correctly predict the in vivo genotoxic and carcinogenic properties of test compounds. Toxicogenomics, i.e. mRNA-profiling, has been proven successful in improving the prediction of genotoxicity in vivo and the understanding of underlying mechanisms. Recently, microRNAs have been discovered as post-transcriptional regulators of mRNAs. It is thus hypothesised that using microRNA response-patterns may further improve current prediction methods. This study aimed at predicting genotoxicity and non-genotoxic carcinogenicity in vivo, by comparing microRNA- and mRNA-based profiles, using a frequently applied in vitro liver model and exposing this to a range of well-chosen prototypical carcinogens. Primary mouse hepatocytes (PMH) were treated for 24 and 48h with 21 chemical compounds [genotoxins (GTX) vs. non-genotoxins (NGTX) and non-genotoxic carcinogens (NGTX-C) versus non-carcinogens (NC)]. MicroRNA and mRNA expression changes were analysed by means of Exiqon and Affymetrix microarray-platforms, respectively. Classification was performed by using Prediction Analysis for Microarrays (PAM). Compounds were randomly assigned to training and validation sets (repeated 10 times). Before prediction analysis, pre-selection of microRNAs and mRNAs was performed by using a leave-one-out t-test. No microRNAs could be identified that accurately predicted genotoxicity or non-genotoxic carcinogenicity in vivo. However, mRNAs could be detected which appeared reliable in predicting genotoxicity in vivo after 24h (7 genes) and 48h (2 genes) of exposure (accuracy: 90% and 93%, sensitivity: 65% and 75%, specificity: 100% and 100%). Tributylinoxide and para-Cresidine were misclassified. Also, mRNAs were identified capable of classifying NGTX-C after 24h (5 genes) as well as after 48h (3 genes) of treatment (accuracy: 78% and 88%, sensitivity: 83% and 83%, specificity: 75% and 93%). Wy-14,643, phenobarbital and ampicillin trihydrate were misclassified. We conclude that genotoxicity and non-genotoxic carcinogenicity probably cannot be accurately predicted based on microRNA profiles. Overall, transcript-based prediction analyses appeared to clearly outperform microRNA-based analyses.
Publication Title
Exploiting microRNA and mRNA profiles generated in vitro from carcinogen-exposed primary mouse hepatocytes for predicting in vivo genotoxicity and carcinogenicity.
Sample Metadata Fields
Specimen part, Compound
View Samples- Mus musculus
- 56 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302), miRCURY LNA microRNA Array, 5th and 7th generation combined - hsa, mmu & rno (miRBase 19.0)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Evaluating microRNA profiles reveals discriminative responses following genotoxic or non-genotoxic carcinogen exposure in primary mouse hepatocytes.
Sample Metadata Fields
Specimen part, Compound
View Samples- Mus musculus
- 56 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The study investigated differential gene expression in primary mouse hepatocyte mRNA following 24 and 48 hours of exposure to aflatoxin B1, cisplatin, benzo(a)pyrene, 2,3,7,8-tetrachloordibenzo-p-dioxine, cyclosporin A or Wy-14,643 or their responsive solvent. Three (four for Wy-14,643) biological replicates per compound/solvent.
Publication Title
Evaluating microRNA profiles reveals discriminative responses following genotoxic or non-genotoxic carcinogen exposure in primary mouse hepatocytes.
Sample Metadata Fields
Specimen part, Compound
View Samples- Homo sapiens
- 35 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The transcriptomics changes induced in the human liver cell line HepG2 by low and high doses of acetaminophen and solvent controls after treatment for 4 time points (12h, 24h, 48h and 72h)
Publication Title
Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain.
Sample Metadata Fields
Specimen part, Cell line, Time
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2), (imblegenhumandnamethylation2.1mdeluxepromoterarray[100929hg19deluxeprommethhx1)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma.
Sample Metadata Fields
Specimen part, Disease, Compound
View Samples