Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis

Ippolito, Danielle L.; AbdulHameed, Mohamed Diwan M.; Tawa, Gregory J.; Baer, Christine E.; Permenter, Matthew G.; McDyre, Bonna C.; Dennis, William E.; Boyle, Molly H.; Hobbs, Cheryl A.; Streicker, Michael A.; Snowden, Bobbi S.; Lewis, John A.; Wallqvist, Anders; Stallings, Jonathan D.

doi:10.1093/toxsci/kfv214

Cited by 43Drug-Induced Hepatotoxicity and ProtectionLiver physiology and pathologyImmunotoxicology and immune responses

Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis

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Ippolito, Danielle L., AbdulHameed, Mohamed Diwan M., Tawa, Gregory J., Baer, Christine E., Permenter, Matthew G., McDyre, Bonna C., Dennis, William E., Boyle, Molly H. +6 more·2016·Toxicological Sciences

DOI 10.1093/toxsci/kfv214

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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.

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Delayed toxicity is associated with changes in gene expression, which can affect the expression of downstream genes.
“What underlay their success was the fact that delayed toxicity is associated with changes in gene expression, which can, in turn, affect the expression of downstream genes [134,135].”
From Machine Learning Based Toxicity Prediction: From Chemical Structural Description to Transcriptome Analysis (2018) · cites this paper as [134]

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Authors: Ippolito, D. L., AbdulHameed, M. D. M., Tawa, G. J., Baer, C. E., Permenter, M. G., McDyre, B. C., Dennis, W. E., Boyle, M. H., Hobbs, C. A., Streicker, M. A., Snowden, B. S., Lewis, J. A., Wallqvist, A., & Stallings, J. D.
Affiliations: United States Army (US)
Telemedicine & Advanced Technology Research Center (US)
Excet (United States) (US)
Oak Ridge Institute for Science and Education (US)
Integrated Laboratory Systems, Inc. (US)
University of Maryland, College Park (US)
Corresponding author: Tawa, Gregory J.
ORCID: AbdulHameed, Mohamed Diwan M.
Tawa, Gregory J.
Permenter, Matthew G.
Boyle, Molly H.
Hobbs, Cheryl A.
Wallqvist, Anders
Stallings, Jonathan D.
Venue: Toxicological Sciences
Publisher: Oxford University Press (OUP)
Published: 2015-09-22
Volume: 149
Issue: 1
Pages: 67-88
ISSN: 1096-0929 (ISSN-L)
1096-6080
DOI: 10.1093/toxsci/kfv214
OpenAlex: W2188699551
Cited by: 43
References: 131
Citations by year: 2026: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 8 · 2018: 7 · 2017: 8 · 2016: 4
FWCI: 7.37
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: public-domain
Locations: Toxicological Sciences (publishedVersion, public-domain)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords: gene expression biomarkers, histopathology, allyl alcohol, carbon tetrachloride, 4,4'-methylenedianiline, bromobenzene, dexamethasone, plasma proteins, fibronectin, ceruloplasmin, vitronectin, IGF binding proteins, alpha2-macroglobulin, liver injury diagnosis
MeSH terms: Animals, Chemotaxis, Glycoproteins, Inflammation, Liver, Liver Cirrhosis, Male, Extracellular Matrix Proteins, Rats, Sprague-Dawley, Computational Biology, Gene Expression Profiling, Intercellular Signaling Peptides and Proteins, Rats, Data Mining

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Gene Expression Patterns Associated With Histopathology in Toxic Liver Fibrosis

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