Genomics and metabolomics of early-stage thioacetamide-induced liver injury: An interspecies study between guinea pig and rat

To study the complex processes involved in liver injuries, researchers rely on animal investigations, using chemically or surgically induced liver injuries, to extrapolate findings and infer human health risks. However, this presents obvious challenges in performing a detailed comparison and validat...

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Published in:Toxicology and applied pharmacology 2021-11, Vol.430, p.115713-115713, Article 115713
Main Authors: Schyman, Patric, Printz, Richard L., Pannala, Venkat R., AbdulHameed, Mohamed Diwan M., Estes, Shanea K., Shiota, Chiyo, Boyd, Kelli Lynn, Shiota, Masakazu, Wallqvist, Anders
Format: Article
Language:English
Subjects:
Animals
Biomarkers
Biomarkers - metabolism
Chemical and Drug Induced Liver Injury - etiology
Chemical and Drug Induced Liver Injury - genetics
Chemical and Drug Induced Liver Injury - metabolism
Chemical and Drug Induced Liver Injury - pathology
Disease Models, Animal
Gene expression
Gene Expression Profiling
Gene Regulatory Networks
Guinea Pigs
Interspecies translation
Liver - metabolism
Liver - pathology
Liver injury
Male
Metabolome
Metabolomics
Rats
Rats, Sprague-Dawley
Species Specificity
Thioacetamide
Time Factors
Transcriptome
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Summary:To study the complex processes involved in liver injuries, researchers rely on animal investigations, using chemically or surgically induced liver injuries, to extrapolate findings and infer human health risks. However, this presents obvious challenges in performing a detailed comparison and validation between the highly controlled animal models and development of liver injuries in humans. Furthermore, it is not clear whether there are species-dependent and -independent molecular initiating events or processes that cause liver injury before they eventually lead to end-stage liver disease. Here, we present a side-by-side study of rats and guinea pigs using thioacetamide to examine the similarities between early molecular initiating events during an acute-phase liver injury. We exposed Sprague Dawley rats and Hartley guinea pigs to a single dose of 25 or 100 mg/kg thioacetamide and collected blood plasma for metabolomic analysis and liver tissue for RNA-sequencing. The subsequent toxicogenomic analysis identified consistent liver injury trends in both genomic and metabolomic data within 24 and 33 h after thioacetamide exposure in rats and guinea pigs, respectively. In particular, we found species similarities in the key injury phenotypes of inflammation and fibrogenesis in our gene module analysis for liver injury phenotypes. We identified expression of several common genes (e.g., SPP1, TNSF18, SERPINE1, CLDN4, TIMP1, CD44, and LGALS3), activation of injury-specific KEGG pathways, and alteration of plasma metabolites involved in amino acid and bile acid metabolism as some of the key molecular processes that changed early upon thioacetamide exposure and could play a major role in the initiation of acute liver injury. •A concurrent study of thioacetamide-induced liver toxicity in rat and guinea pigs.•Transcriptomics and metabolomics indicate similarities in liver response.•Gene module analysis reveal phenotypic signatures of inflammation and fibrogenisis.•Metabolites in lipid and aminoacid pathways can be potential early indicators.
ISSN:0041-008X
1096-0333
1096-0333
DOI:10.1016/j.taap.2021.115713