Guest editorial

Highlight report: Toxicogenomics atlas of rat hepatotoxicants

Florian Seidel1[*]

1Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystr. 67, 44139 Dortmund

EXCLI J 2018;17:Doc1196

 

Transcriptomics has developed into an invaluable tool in chemical hazard identification (Godoy et al., 2013[5], 2015[7], 2018[6]; Lohr et al., 2015[13]; Ellinger-Ziegelbauer et al., 2011[3]; Waldmann et al., 2014[20]; Balmer et al., 2014[1]). The pattern of deregulated genes in exposed cells gives first evidence of the involved mechanisms of toxicity (Rempel et al., 2015[15]; Stemmer et al., 2007[17]; Leist et al., 2017[12]; Rodrigues et al., 2018[16]). A milestone in this field of research was the establishment of the toxicogenomics directory of chemically exposed human hepatocytes (Grinberg et al., 2014[10]). A key message of this study was that stereotypical expression responses exist, whereby a similar set of genes is deregulated after exposure of human hepatocytes to different compounds. A relatively large fraction of these stereotypical stress response genes are also up- or downregulated in human liver disease, such as non-alcoholic steatohepatitis, cirrhosis or hepatocellular cancer (Grinberg et al., 2014[10]). While the human toxicogenomics directory has been widely used for follow-up studies, a similar database for rat hepatocytes has not yet been established.

To bridge this gap, Marianna Grinberg and colleagues from Dortmund University recently published the corresponding directory of rat hepatotoxicants (Grinberg et al., 2018[9]). Laboratory animals offer the advantage that liver tissue after exposure to test compounds can be compared to cultivated hepatocytes exposed to the same compounds. For this purpose, the authors analyzed microarray expression data from 162 test substances that were tested in a concentration-dependent manner in rat livers in vivo and in cultivated hepatocytes. Based on this comprehensive data set genes were analyzed that showed a similar response in vitro and in vivo. Next, genes were identified that were most frequently deregulated by the test compounds. This resulted in seven genes with the highest coverage of compounds (Cyp1a1, Vgt2b1, Cdkn1a, Mdm2, Aldh1a1, Cyp4a3 and Ehhadh). Analysis of these genes in hepatocytes incubated with compounds not present in the above mentioned set of 162 test substances showed that at least one of these seven genes was also deregulated in the set of independent compounds.

Currently, hepatotoxicity represents a major research field in toxicology (Vartak et al., 2016[19]; Godoy et al., 2016[8]; Bolt, 2017[2]; Hassan, 2016[11]). Techniques for the reliable identification of compounds that will induce liver injury of humans are urgently needed (Stöber, 2016[18]; Ghallab, 2017[4]; Paech et al., 2017[14]). In this field of research the recently established human and rat toxicogenomics directories represent invaluable resources.

 

References

1. Balmer NV, Klima S, Rempel E, Ivanova VN, Kolde R, Weng MK, et al. From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014;88:1451-68.
2. Bolt HM. Highlight report: The pseudolobule in liver fibrosis. EXCLI J. 2017;16:1321-2.
3. Ellinger-Ziegelbauer H, Adler M, Amberg A, Brandenburg A, Callanan JJ, Connor S, et al. The enhanced value of combining conventional and „omics“ analyses in early assessment of drug-induced hepatobiliary injury. Toxicol Appl Pharmacol. 2011;252:97-111.
4. Ghallab A. Highlight report: Metabolomics in hepatotoxicity testing. EXCLI J. 2017;16:1323-5.
5. Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol. 2013;87:1315-530.
6. Godoy P, Schmidt-Heck W, Hellwig B, Nell P, Feuerborn D, Rahnenführer J, et al. Assessment of stem cell differentiation on genome-wide expression profiles. Philos Trans R. Soc Lond B Biol Sci. 2018;373(1750).
7. Godoy P, Schmidt-Heck W, Natarajan K, Lucendo-Villarin B, Szkolnicka D, Asplund A, et al. Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells. J Hepatol. 2015;63:934-42.
8. Godoy P, Widera A, Schmidt-Heck W, Campos G, Meyer C, Cadenas C, et al. Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue. Arch Toxicol. 2016;90:2513-29.
9. Grinberg M, Stöber RM, Albrecht W, Edlund K, Schug M, Godoy P, et al. Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes. Arch Toxicol. 2018;92:3517-33.
10. Grinberg M, Stöber RM, Edlund K, Rempel E, Godoy P, Reif R, et al. Toxicogenomics directory of chemically exposed human hepatocytes. Arch Toxicol. 2014;88:2261-87.
11. Hassan R. Possibilities and limitations of intravital imaging. EXCLI J. 2016;15:872-4.
12. Leist M, Ghallab A, Graepel R, Marchan R, Hassan R, Bennekou SH, et al. Adverse outcome pathways: opportunities, limitations and open questions. Arch Toxicol. 2017;91:3477-505.
13. Lohr M, Hellwig B, Edlund K, Mattsson JS, Botling J, Schmidt M, et al. Identification of sample annotation errors in gene expression datasets. Arch Toxicol. 2015;89:2265-72.
14. Paech F, Messner S, Spickermann J, Wind M, Schmitt-Hoffmann AH, Witschi AT, et al. Mechanisms of hepatotoxicity associated with the monocyclic β-lactam antibiotic BAL30072. Arch Toxicol. 2017;91:3647-62.
15. Rempel E, Hoelting L, Waldmann T, Balmer NV, Schildknecht S, Grinberg M, et al. A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015;89:1599-618.
16. Rodrigues RM, Kollipara L, Chaudhari U, Sachinidis A, Zahedi RP, Sickmann A, et al. Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018;92:1939-52.
17. Stemmer K, Ellinger-Ziegelbauer H, Ahr HJ, Dietrich DR. Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis. Cancer Res. 2007;67:4052-68.
18. Stöber R. Pathophysiology of cholestatic liver disease and its relevance for in vitro tests of hepatotoxicity. EXCLI J. 2016;15:870-1.
19. Vartak N, Damle-Vartak A, Richter B, Dirsch O, Dahmen U, Hammad S, et al. Cholestasis-induced adaptive remodeling of interlobular bile ducts. Hepatology. 2016;63:951-64.
20. Waldmann T, Rempel E, Balmer NV, König A, Kolde R, Gaspar JA, et al. Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014;27:408-20.
 
 
 

[*] Corresponding Author:

Florian Seidel, Leibniz Research Centre for Working Environment and Human Factors (IfADo), Ardeystr. 67, 44139 Dortmund, eMail: seidelf@ifado.de