Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes

Marianna Grinberg; Regina M Stöber; Wiebke Albrecht; Karolina Edlund; Markus Schug; Patricio Godoy; Cristina Cadenas; Rosemarie Marchan; Alfonso Lampen; Albert Braeuning; Thorsten Buhrke; Marcel Leist; Axel Oberemm; Birte Hellwig; Hennicke Kamp; Iain Gardner; Sylvia Escher; Olivier Taboureau; Alejandro Aguayo-Orozco; Agapios Sachinidis; Heidrun Ellinger-Ziegelbauer; Jörg Rahnenführer; Jan G Hengstler

doi:10.1007/s00204-018-2352-3

Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes

Marianna Grinberg, Regina M Stöber, Wiebke Albrecht, Karolina Edlund, Markus Schug, Patricio Godoy, Cristina Cadenas, Rosemarie Marchan, Alfonso Lampen, Albert Braeuning, Thorsten Buhrke, Marcel Leist, Axel Oberemm, Birte Hellwig, Hennicke Kamp, Iain Gardner, Sylvia Escher, Olivier Taboureau, Alejandro Aguayo-Orozco, Agapios SachinidisHeidrun Ellinger-Ziegelbauer, Jörg Rahnenführer, Jan G Hengstler

Disease Systems Biology Program

24 Citations (Scopus)

Abstract

Transcriptomics is developing into an invaluable tool in toxicology. The aim of this study was, using a transcriptomics approach, to identify genes that respond similar to many different chemicals (including drugs and industrial compounds) in both rat liver in vivo and in cultivated hepatocytes. For this purpose, we analyzed Affymetrix microarray expression data from 162 compounds that were previously tested in a concentration-dependent manner in rat livers in vivo and in rat hepatocytes cultivated in sandwich culture. These data were obtained from the Japanese Toxicogenomics Project (TGP) and North Rhine-Westphalian (NRW) data sets, which represent 138 and 29 compounds, respectively, and have only 5 compounds in common between them. The in vitro gene expression 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, and named in vitro-in vivo consensus genes. Interestingly, the in vivo-in vitro consensus genes overlapped to a remarkable extent between both data sets, and were 21-times (upregulated genes) or 12-times (down-regulated genes) enriched compared to random expectation. Finally, the genes in the TGP and NRW overlap were used to identify the upregulated genes with the highest compound coverage, resulting in a seven-gene set of Cyp1a1, Ugt2b1, Cdkn1a, Mdm2, Aldh1a1, Cyp4a3, and Ehhadh. This seven-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 seven-gene set identified in the present study responds similarly in vitro and in vivo to a wide range of different chemicals. Despite these promising results with the seven-gene set, transcriptomics with cultivated rat hepatocytes remains a challenge, because in general many genes are up- or downregulated by in vitro culture per se, respond differently to test compounds in vitro and in vivo, and/or show higher variability in the in vitro system compared to the corresponding in vivo data.

Original language	English
Journal	Archives of Toxicology
Volume	92
Issue number	12
Pages (from-to)	3517-3533
Number of pages	17
ISSN	0340-5761
DOIs	https://doi.org/10.1007/s00204-018-2352-3
Publication status	Published - Dec 2018

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Grinberg, M., Stöber, R. M., Albrecht, W., Edlund, K., Schug, M., Godoy, P., Cadenas, C., Marchan, R., Lampen, A., Braeuning, A., Buhrke, T., Leist, M., Oberemm, A., Hellwig, B., Kamp, H., Gardner, I., Escher, S., Taboureau, O., Aguayo-Orozco, A., ... Hengstler, J. G. (2018). Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes. Archives of Toxicology, 92(12), 3517-3533. https://doi.org/10.1007/s00204-018-2352-3

Grinberg, M, Stöber, RM, Albrecht, W, Edlund, K, Schug, M, Godoy, P, Cadenas, C, Marchan, R, Lampen, A, Braeuning, A, Buhrke, T, Leist, M, Oberemm, A, Hellwig, B, Kamp, H, Gardner, I, Escher, S, Taboureau, O , Aguayo-Orozco, A, Sachinidis, A, Ellinger-Ziegelbauer, H, Rahnenführer, J & Hengstler, JG 2018, 'Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes', Archives of Toxicology, vol. 92, no. 12, pp. 3517-3533. https://doi.org/10.1007/s00204-018-2352-3

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title = "Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes",

abstract = "Transcriptomics is developing into an invaluable tool in toxicology. The aim of this study was, using a transcriptomics approach, to identify genes that respond similar to many different chemicals (including drugs and industrial compounds) in both rat liver in vivo and in cultivated hepatocytes. For this purpose, we analyzed Affymetrix microarray expression data from 162 compounds that were previously tested in a concentration-dependent manner in rat livers in vivo and in rat hepatocytes cultivated in sandwich culture. These data were obtained from the Japanese Toxicogenomics Project (TGP) and North Rhine-Westphalian (NRW) data sets, which represent 138 and 29 compounds, respectively, and have only 5 compounds in common between them. The in vitro gene expression 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, and named in vitro-in vivo consensus genes. Interestingly, the in vivo-in vitro consensus genes overlapped to a remarkable extent between both data sets, and were 21-times (upregulated genes) or 12-times (down-regulated genes) enriched compared to random expectation. Finally, the genes in the TGP and NRW overlap were used to identify the upregulated genes with the highest compound coverage, resulting in a seven-gene set of Cyp1a1, Ugt2b1, Cdkn1a, Mdm2, Aldh1a1, Cyp4a3, and Ehhadh. This seven-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 seven-gene set identified in the present study responds similarly in vitro and in vivo to a wide range of different chemicals. Despite these promising results with the seven-gene set, transcriptomics with cultivated rat hepatocytes remains a challenge, because in general many genes are up- or downregulated by in vitro culture per se, respond differently to test compounds in vitro and in vivo, and/or show higher variability in the in vitro system compared to the corresponding in vivo data.",

author = "Marianna Grinberg and St{\"o}ber, {Regina M} and Wiebke Albrecht and Karolina Edlund and Markus Schug and Patricio Godoy and Cristina Cadenas and Rosemarie Marchan and Alfonso Lampen and Albert Braeuning and Thorsten Buhrke and Marcel Leist and Axel Oberemm and Birte Hellwig and Hennicke Kamp and Iain Gardner and Sylvia Escher and Olivier Taboureau and Alejandro Aguayo-Orozco and Agapios Sachinidis and Heidrun Ellinger-Ziegelbauer and J{\"o}rg Rahnenf{\"u}hrer and Hengstler, {Jan G}",

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T1 - Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes

AU - Grinberg, Marianna

AU - Stöber, Regina M

AU - Albrecht, Wiebke

AU - Edlund, Karolina

AU - Schug, Markus

AU - Godoy, Patricio

AU - Cadenas, Cristina

AU - Marchan, Rosemarie

AU - Lampen, Alfonso

AU - Braeuning, Albert

AU - Buhrke, Thorsten

AU - Leist, Marcel

AU - Oberemm, Axel

AU - Hellwig, Birte

AU - Kamp, Hennicke

AU - Gardner, Iain

AU - Escher, Sylvia

AU - Taboureau, Olivier

AU - Aguayo-Orozco, Alejandro

AU - Sachinidis, Agapios

AU - Ellinger-Ziegelbauer, Heidrun

AU - Rahnenführer, Jörg

AU - Hengstler, Jan G

PY - 2018/12

Y1 - 2018/12

N2 - Transcriptomics is developing into an invaluable tool in toxicology. The aim of this study was, using a transcriptomics approach, to identify genes that respond similar to many different chemicals (including drugs and industrial compounds) in both rat liver in vivo and in cultivated hepatocytes. For this purpose, we analyzed Affymetrix microarray expression data from 162 compounds that were previously tested in a concentration-dependent manner in rat livers in vivo and in rat hepatocytes cultivated in sandwich culture. These data were obtained from the Japanese Toxicogenomics Project (TGP) and North Rhine-Westphalian (NRW) data sets, which represent 138 and 29 compounds, respectively, and have only 5 compounds in common between them. The in vitro gene expression 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, and named in vitro-in vivo consensus genes. Interestingly, the in vivo-in vitro consensus genes overlapped to a remarkable extent between both data sets, and were 21-times (upregulated genes) or 12-times (down-regulated genes) enriched compared to random expectation. Finally, the genes in the TGP and NRW overlap were used to identify the upregulated genes with the highest compound coverage, resulting in a seven-gene set of Cyp1a1, Ugt2b1, Cdkn1a, Mdm2, Aldh1a1, Cyp4a3, and Ehhadh. This seven-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 seven-gene set identified in the present study responds similarly in vitro and in vivo to a wide range of different chemicals. Despite these promising results with the seven-gene set, transcriptomics with cultivated rat hepatocytes remains a challenge, because in general many genes are up- or downregulated by in vitro culture per se, respond differently to test compounds in vitro and in vivo, and/or show higher variability in the in vitro system compared to the corresponding in vivo data.

AB - Transcriptomics is developing into an invaluable tool in toxicology. The aim of this study was, using a transcriptomics approach, to identify genes that respond similar to many different chemicals (including drugs and industrial compounds) in both rat liver in vivo and in cultivated hepatocytes. For this purpose, we analyzed Affymetrix microarray expression data from 162 compounds that were previously tested in a concentration-dependent manner in rat livers in vivo and in rat hepatocytes cultivated in sandwich culture. These data were obtained from the Japanese Toxicogenomics Project (TGP) and North Rhine-Westphalian (NRW) data sets, which represent 138 and 29 compounds, respectively, and have only 5 compounds in common between them. The in vitro gene expression 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, and named in vitro-in vivo consensus genes. Interestingly, the in vivo-in vitro consensus genes overlapped to a remarkable extent between both data sets, and were 21-times (upregulated genes) or 12-times (down-regulated genes) enriched compared to random expectation. Finally, the genes in the TGP and NRW overlap were used to identify the upregulated genes with the highest compound coverage, resulting in a seven-gene set of Cyp1a1, Ugt2b1, Cdkn1a, Mdm2, Aldh1a1, Cyp4a3, and Ehhadh. This seven-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 seven-gene set identified in the present study responds similarly in vitro and in vivo to a wide range of different chemicals. Despite these promising results with the seven-gene set, transcriptomics with cultivated rat hepatocytes remains a challenge, because in general many genes are up- or downregulated by in vitro culture per se, respond differently to test compounds in vitro and in vivo, and/or show higher variability in the in vitro system compared to the corresponding in vivo data.

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DO - 10.1007/s00204-018-2352-3

M3 - Journal article

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SN - 0340-5761

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JO - Archives of Toxicology

JF - Archives of Toxicology

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ER -

Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes

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