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Toxicol Sci. 2016 Jan;149(1):67-88. doi: 10.1093/toxsci/kfv214. Epub 2015 Sep 22.

Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis.

Author information

1
*The Environmental Health Program, The United States Army Center for Environmental Health Research (USACEHR), Fort Detrick, Maryland 21702-5010;
2
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, Maryland 21702;
3
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, Maryland 21702; Danielle.L.Ippolito2.civ@mail.mil.
4
Excet, Inc. and.
5
Oak Ridge Institute for Science and Education, Frederick, Maryland 21702-5010;
6
Integrated Laboratory Systems, Research Triangle Park, North Carolina 27709; and.
7
Maryland Institute for Applied Environmental Health, School of Public Health, University of Maryland, College Park, Maryland 20742.
8
*The Environmental Health Program, The United States Army Center for Environmental Health Research (USACEHR), Fort Detrick, Maryland 21702-5010; Danielle.L.Ippolito2.civ@mail.mil.

Abstract

Toxic industrial chemicals induce liver injury, which is difficult to diagnose without invasive procedures. Identifying indicators of end organ injury can complement exposure-based assays and improve predictive power. A multiplexed approach was used to experimentally evaluate a panel of 67 genes predicted to be associated with the fibrosis pathology by computationally mining DrugMatrix, a publicly available repository of gene microarray data. Five-day oral gavage studies in male Sprague Dawley rats dosed with varying concentrations of 3 fibrogenic compounds (allyl alcohol, carbon tetrachloride, and 4,4'-methylenedianiline) and 2 nonfibrogenic compounds (bromobenzene and dexamethasone) were conducted. Fibrosis was definitively diagnosed by histopathology. The 67-plex gene panel accurately diagnosed fibrosis in both microarray and multiplexed-gene expression assays. Necrosis and inflammatory infiltration were comorbid with fibrosis. ANOVA with contrasts identified that 51 of the 67 predicted genes were significantly associated with the fibrosis phenotype, with 24 of these specific to fibrosis alone. The protein product of the gene most strongly correlated with the fibrosis phenotype PCOLCE (Procollagen C-Endopeptidase Enhancer) was dose-dependently elevated in plasma from animals administered fibrogenic chemicals (P < .05). Semiquantitative global mass spectrometry analysis of the plasma identified an additional 5 protein products of the gene panel which increased after fibrogenic toxicant administration: fibronectin, ceruloplasmin, vitronectin, insulin-like growth factor binding protein, and α2-macroglobulin. These results support the data mining approach for identifying gene and/or protein panels for assessing liver injury and may suggest bridging biomarkers for molecular mediators linked to histopathology.

KEYWORDS:

bioinformatics; biomarkers; fibrosis; histopathology; toxic liver injury; transcriptomics

PMID:
26396155
DOI:
10.1093/toxsci/kfv214
[Indexed for MEDLINE]

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