ToxPanel

ToxPanel for Assessing Liver and Kidney Injury

ToxPanel is a web-based tool to assess liver and kidney injury from in vitro or in vivo genomic data. In the field of toxicogenomics, a common assumption is that toxicity is associated with a change in the expression of either a single gene or a set of genes (i.e., a module), and that a certain injury endpoint causes a specific gene-expression response—that is, a gene signature.

Using a toxicogenomics approach, we have derived 11 liver and 8 kidney injury modules [1] from the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) database [2]. Each injury module is uniquely associated with a specific organ-injury phenotype (see Tables 1 and 2). TG-GATEs contains gene-expression data from Sprague-Dawley rats exposed to different chemicals for 4 to 29 days, with corresponding documented histopathological injury phenotypes.

Table 1. List of liver-injury module phenotypes, grouped into general classes with the number of genes in each module.

Inflammation		Degeneration		Proliferation
Fibrogenesis	48	Anisonucleosis	65	Bile duct proliferation	16
Cellular infiltration	25	Nuclear alteration	111	Oval cell proliferation	126
Hematopoiesis	27	Cytoplasmic alteration	18	Cellular foci	35
Single cell necrosis	11	Granular degeneration	18

Table 2. List of kidney-injury module phenotypes with the number of genes in each module.

Kidney injury module
Necrosis	18
Fibrogenesis	125
Cellular infiltration	42
Casts (hyaline)	23
Hypertrophy	16
Degeneration	65
Dilatation	8
Inclusion bodies (cytoplasmic)	40

We have validated these injury modules in vivo by treating Sprague-Dawley rats with thioacetamide [3], an organosulfur compound extensively used in animal studies as a fibrogenesis-promoting liver toxicant. Our ToxPanel approach correctly identified cellular infiltration and fibrogenesis as the primary liver-injury phenotypes induced by thioacetamide (Figure 1).

Figure 1. Gene-expression changes in the rat liver 24 hours after thioacetamide (TAA) [100 mg/g] exposure. TAA is an organosulfur compound extensively used in animal studies as a fibrogenesis-promoting liver toxicant. Our ToxPanel correctly identified cellular infiltration and fibrogenesis as primary liver-injury phenotypes after 24 h. ToxPanel can also predict in vivo injury endpoints from in vitro RNA sequence (RNA-seq) data with a strong correlation (R2 > 0.6) [4]. In this study, we compared in vivo rat data with in vitro cellular data 24 hours after treatment with TAA-S-oxide, the metabolized form of TAA required to induce toxicity in vitro. The-top ranked liver-injury modules identified by our in vitro studies agreed with those identified in vivo, indicating that in vitro cellular responses were also associated with changes in the expression of fibrogenesis-related gene sets. These results suggest that, the predictions of our co-expressed gene-module approach are more robust than those of gene signatures for specific pathologies, because they rely on groups of genes rather than individual genes.

Our liver- and kidney-injury modules can be downloaded here.

References

J.A. Te, M.D.M. AbdulHameed, A. Wallqvist, Systems toxicology of chemically induced liver and kidney injuries: histopathology‐associated gene co‐expression modules, J. Appl. Toxicol. 36 (2016) 1137-1149.
Y. Igarashi, N. Nakatsu, T. Yamashita, A. Ono, Y. Ohno, T. Urushidani, H. Yamada, Open TG-GATEs: a large-scale toxicogenomics database, Nucleic Acids Res. 43 (2015) D921-D927.
P. Schyman, R.L. Printz, S.K. Estes, K.L. Boyd, M. Shiota, A. Wallqvist, Identification of the toxicity pathways associated with thioacetamide-induced injuries in rat liver and kidney, Front. Pharmacol. 9 (2018) 1272.
P. Schyman, R.L. Printz, S.K. Estes, T.P. O’Brien, M. Shiota, A. Wallqvist, Assessing chemical-induced liver injury in vivo from in vitro gene expression data in the rat: the case of thioacetamide toxicity, Front. Genet. 10 (2019) 1233.