Systems toxicology of chemically induced liver and kidney injuries: histopathology-associated gene co-expression modules

J Appl Toxicol. 2016 Sep;36(9):1137-49. doi: 10.1002/jat.3278. Epub 2016 Jan 4.


Organ injuries caused by environmental chemical exposures or use of pharmaceutical drugs pose a serious health risk that may be difficult to assess because of a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific histopathology outcomes via biomarkers will provide a foundation for designing precise and robust diagnostic tests. We identified co-expressed genes (modules) specific to injury endpoints using the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) - a toxicogenomics database containing organ-specific gene expression data matched to dose- and time-dependent chemical exposures and adverse histopathology assessments in Sprague-Dawley rats. We proposed a protocol for selecting gene modules associated with chemical-induced injuries that classify 11 liver and eight kidney histopathology endpoints based on dose-dependent activation of the identified modules. We showed that the activation of the modules for a particular chemical exposure condition, i.e., chemical-time-dose combination, correlated with the severity of histopathological damage in a dose-dependent manner. Furthermore, the modules could distinguish different types of injuries caused by chemical exposures as well as determine whether the injury module activation was specific to the tissue of origin (liver and kidney). The generated modules provide a link between toxic chemical exposures, different molecular initiating events among underlying molecular pathways and resultant organ damage. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.

Keywords: adverse outcome pathways; co-expression modules; hepatotoxicity; histopathology; nephrotoxicity; systems toxicology; toxicogenomics.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Databases, Factual
  • Dose-Response Relationship, Drug
  • Endpoint Determination
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Genomics
  • Kidney / drug effects*
  • Kidney / metabolism
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Models, Biological
  • Principal Component Analysis
  • Rats
  • Rats, Sprague-Dawley
  • Toxicogenetics
  • Xenobiotics / toxicity*


  • Biomarkers
  • Xenobiotics