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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2018.00636

Comparison of RNA-Seq and Microarray Gene Expression Platforms for the Toxicogenomic Evaluation of Liver from Short-Term Rat Toxicity Studies

 Mohan S. Rao1*, Terry R. Van Vleet1,  Rita Ciurlionis1, Wayne R. Buck1, Scott W. Mittelstadt1,  Eric A. Blomme1 and Micheal J. Liguori1
  • 1AbbVie (United States), United States

Gene expression profiling is a useful tool to predict and interrogate mechanisms of toxicity. RNA-Seq technology has emerged as an attractive alternative to traditional microarray platforms for conducting transcriptional profiling. The objective of this work was to compare both transcriptomic platforms to determine whether RNA-Seq offered significant advantages over microarrays for toxicogenomic studies. RNA samples from the livers of rats treated for 5 days with five tool hepatotoxicants (-naphthylisothiocyanate/ANIT, carbon tetrachloride/CCl4, methylenedianiline/MDA, acetaminophen/APAP, and diclofenac/DCLF) were analyzed with both gene expression platforms (RNA-Seq and microarray). Data were compared to determine any potential added scientific (i.e. better biological or toxicological insight) value offered by RNA-Seq compared to microarrays. RNA-Seq identified more differentially expressed protein-coding genes and provided a wider quantitative range of expression level changes when compared to microarrays. Both platforms identified a larger number of differentially expressed genes (DEGs) in livers of rats treated with ANIT, MDA and CCl4 compared to APAP and DCLF, in agreement with the severity of histopathological findings. Approximately 78% of DEGs identified with microarrays overlapped with RNA-Seq data, with a Spearman’s correlation of 0.7 to 0.83. Consistent with the mechanisms of toxicity of ANIT, APAP, MDA and CCl4, both platforms identified dysregulation of liver relevant pathways such as Nrf2, cholesterol biosynthesis, eiF2, hepatic cholestasis, glutathione and LPS/IL-1 mediated RXR inhibition. RNA-Seq data showed additional DEGs that not only significantly enriched these pathways, but also suggested modulation of additional liver relevant pathways. In addition, RNA-Seq enabled the identification of non-coding DEGs that offer a potential for improved mechanistic clarity. Overall, these results indicate that RNA-Seq is an acceptable alternative platform to microarrays for rat toxicogenomic studies with several advantages. Because of its wider dynamic range as well as its ability to identify a larger number of DEGs, RNA-Seq may generate more insight into mechanisms of toxicity. However, more extensive reference data will be necessary to fully leverage these additional RNA-Seq data, especially for non-coding sequences.

Keywords: RNAseq analysis, Microarray, in vivo, Hepatotoxicants, toxicogenomics, non-coding RNAs, DEG (differentially expressed genes)

Received: 15 Sep 2018; Accepted: 27 Nov 2018.

Edited by:

Pierre R. Bushel, National Institute of Environmental Health Sciences (NIEHS), United States

Reviewed by:

Scott Auerbach, National Institute of Environmental Health Sciences (NIEHS), United States
Gabriele Bucci, San Raffaele Hospital (IRCCS), Italy  

Copyright: © 2018 Rao, Van Vleet, Ciurlionis, Buck, Mittelstadt, Blomme and Liguori. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Mohan S. Rao, AbbVie (United States), North Chicago, Illinois, United States, mohan.rao@abbvie.com