Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes
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PROVIDER: PRJNA490737 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptomics is developing into an invaluable tool in toxicology. The aim of this study was, using a transcriptomics approach, to identify genes that respond similarly to chemicals (including drugs and industrial compounds) in both rat liver in vivo and in cultivated hepatocytes, which are up- or downregulated by many different test compounds. For this purpose, we analyzed Affymetrix gene array data from 162 compounds that were previously tested in a concentration-dependent manner in rat livers in vivo and rat hepatocytes cultivated in sandwich culture. These data were obtained from the Japanese Toxicogenomics (TGP) and North-Rhine-Westphalian (NRW) data sets, which consist of 138 and 29 compounds, respectively, and have 5 mutual compounds between them. The in vitro gene array data from the NRW data set were generated in the present study, while TGP is publicly available. For each of the data sets, the overlap between up- or down-regulated genes in vitro and in vivo was identified, further named in vitro-in vivo consensus genes. Interestingly, an overlap of in vivo-in vitro consensus genes was obtained between both data sets, which were 21-times (up-regulated genes) or 12-times (down-regulated genes) en-riched compared to random expectation. This is remarkable since the TGP and NRW data sets contained only five mutual compounds. Finally, the genes in the TGP and NRW overlap were used to identify the upregulated genes with the highest com-pound coverage, resulting in a 7-gene set of Cyp1a1, Ugt2b1, Cdkn1a, Mdm2, Aldh1a1, Cyp4a3, and Ehhad. This 7-gene set was then successfully tested with structural analogues of valproic acid that are not present in the TGP and NRW data sets. In conclusion, the 7-gene set identified in the present study responds similarly in vitro and in vivo and is induced by a wide range of different chemicals. Despite these results, transcriptomics with cultivated rat hepatocytes remains a challenge, because many genes are up- or downregulated by the culture conditions, respond differently to test compounds in vitro and in vivo, and shows a higher variability in the in vitro system compared to the corresponding in vivo data. The raw data for the TGP study are available at https://toxico.nibiohn.go.jp/ For the normalization of the entire set of expression arrays, the RMA algorithm was used. The results are summarized in the publicly available toxicotranscriptomics directory (http://wiki.toxbank.net/toxicogenomics-map/).
2018-09-14 | GSE119933 | GEO
Project description:The development of more complex but reliable systems for compound testing in a pharmaceutical context is a challenging task to date. Three dimensional (3D), organ mimetic cell culture is aiming to become an alternative to common two dimensional (2D) cell culture or animal testing in that field. We developed a biocompatible 3D cell culture environment for a 3D hepatocyte cell culture that enables cellular maintenance in a polycarbonate scaffold structure. Our data indicate that an actively perfused three dimensional cell culture displays a more pronounced metabolic genotype than statically cultivated hepatocytes.
2013-08-31 | GSE44580 | GEO
Project description:The development of more complex but reliable systems for compound testing in a pharmaceutical context is a challenging task to date. Three dimensional (3D), organ mimetic cell culture is aiming to become an alternative to common two dimensional (2D) cell culture or animal testing in that field. We developed a biocompatible 3D cell culture environment for a 3D hepatocyte cell culture that enables cellular maintenance in a polycarbonate scaffold structure. Our data indicate that an actively perfused three dimensional cell culture displays a more pronounced metabolic genotype than statically cultivated hepatocytes. Human hepatocytes of three donors were cultivated for five days under 2D and 3D statical and perfused conditions. Cultivation was started with 0.25 x106 in 2D and with 1x 106 vital cells for the 3D experiments. The day of seeding was defined as d0. The groups were classified as follows: 2D i.e.monolayer cultures, 3D i.e. statical 3D culture and BR denotes perfused 3D culture of hepatocytes. The perfusable bioreactor system was operated using a peristaltic pump. It houses the MatriGrid, a polycarbonate based microporous cellular support. For 3Dstatic cultivation, cell- inoculated MatriGrids were placed in wells of a 24 wells plate. Microarray experiments of three 2D (i.e. control), three 3D statically and three actively perfused 3D cultivations, respectively, were performed at SIRS-Lab GmbH (SIRS-Lab GmbH, Jena, Germany) according to the manufacturerM-bM-^@M-^Ys instructions (Illumina, San Diego, CA). Altogether, 8 RNA samples of hepatocyte cultures and an internal control RNA were hybridized on two HumanHT-12 v4 Expression BeadChips.
2013-03-31 | E-GEOD-44580 | biostudies-arrayexpress
Project description:We investigated the effects of the flutamide (FLU) -induced liver injury in primary rat hepatocytes using our liver microfluidic biochips. Flutamide is used a non-steroidal anti-androgenic drug. Two flutamide concentrations, 10M-BM-5M and 100M-BM-5M, were used to expose the hepatocytes for 24h under perfusion. Primary rat hepatocytes were cultivated in microfluidic biochips and treated with 10 and 100M-BM-5M of flutamide for 24h
2013-12-01 | E-GEOD-44317 | biostudies-arrayexpress
Project description:A toxicogenomics approach was used to qualitatively and quantitatively compare gene expression changes in rat primary hepatocytes exposed to 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) or 2,3,7,8-tetrachlorodibenzofuran (TCDF). Hepatocytes from five individual rats were exposed for 24 hours to 11 concentrations of each chemical ranging from 0.00001 nM to 100 nM and a vehicle control.
2014-01-01 | GSE49473 | GEO
Project description:A toxicogenomics approach was used to qualitatively and quantitatively compare the gene expression changes in human and rat primary hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hepatocytes from five individual rats and five individual humans were exposed for 24 hours to 11 concentrations of TCDD ranging from 0.00001 nM to 100 nM and a vehicle control. Gene expression changes were analyzed using whole genome microarrays.
2012-02-03 | GSE34250 | GEO
Project description:DrugMatrix is a comprehensive rat toxicogenomics database and analysis tool developed to facilitate the integration of toxicogenomics into hazard assessment. Using the whole genome and a diverse set of compounds allows a comprehensive view of most pharmacological and toxicological questions and is applicable to other situations such as disease and development. Complete Drug Matrix dataset for primary rat hepatocytes. Cells were exposed to toxicants in culture medium and harvested after 0.67 or 1 day.
2014-05-27 | E-GEOD-57805 | biostudies-arrayexpress
Project description:The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. Conclusion: the present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo. expression profiles of sandwich-cultured primary human hepatocytes exposed to 5 mM and 10 mM acetaminophen were used in a parallelogram approach in order to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Keywords: Toxicogenomics, dose response
2009-01-01 | GSE13430 | GEO
Project description:A toxicogenomics approach was used to qualitatively and quantitatively compare gene expression changes in rat primary hepatocytes exposed to 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) or 2,3,7,8-tetrachlorodibenzofuran (TCDF). Hepatocytes from five individual rats were exposed for 24 hours to 11 concentrations of each chemical ranging from 0.00001 nM to 100 nM and a vehicle control. 115 microarrays representing primary hepatocytes from 5 rats, each exposed to 11 doses of each chemical (PeCDF and TCDF) and vehicle controls. Arrays were completed with a one-color design.
2014-01-01 | E-GEOD-49473 | biostudies-arrayexpress
Project description:The Toxicogenomics Project was a 5-year collaborative project (2002-2007) by a consortium comprising the Japanese government and several pharmaceutical companies. The project produced the 'Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system' (TG-GATEs), a large-scale database of transcriptomics and pathology data potentially useful for predicting the toxicity of new chemical entities. Conventional in vivo toxicology data was collected from single dose and repeat dosing studies on rats, and gene expression measured for the liver (and kidney in some cases). To provide information on species differences, gene expression was also measured in rat and human hepatocytes treated with the chemicals in vitro. Approximately 130 chemicals, primarily medicinal compounds, were tested at multipe doses. Gene expression was analysed using Affymetrix GeneChip arrays. The gene expression data has been submitted in four parts: in vivo single dose (E-MTAB-799), in vivo repeat dosing, in vitro rat (E-MTAB-797) and in vitro human (E-MTAB-798). This submission comprises the in vivo, repeat dosing studies. If publishing results based on this data, please cite the full project name 'Toxicogenomics Project and Toxicogenomics Informatics Project', the database name 'Open TG-GATEs' and the URL 'http://toxico.nibio.go.jp'. Please note that the European Bioinformatics Institute (EBI) was not involved in the Toxicogenomics Project in any way, acting only to submit the transcriptomics data to Array Express. Queries about the project can be addressed to the consortium directly via 'opentggates@nibio.go.jp'. This dataset is part of the TransQST collection.
2012-02-10 | E-MTAB-800 | biostudies-arrayexpress