Comparative Proteomic Analysis of Liver Steatosis and Fibrosis after Oral Hepatotoxicant Administration in Sprague-Dawley Rats

McDyre, Bonna C.; AbdulHameed, Mohamed Diwan M.; Permenter, Matthew G.; Dennis, William E.; Baer, Christine E.; Koontz, Jason M; Boyle, Molly H.; Wallqvist, Anders; Lewis, John A.; Ippolito, Danielle L.

doi:10.1177/0192623317747549

Cited by 7 publications

(5 citation statements)

References 60 publications

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“…This was not accompanied by cell damage in hepatocytes, bile duct epithelium, or inflammatory cell infiltration. The liver enzymes ALAT and ASAT that are abnormally altered in the setting of liver damage (Whalan 2015; Giannini, Testa, and Savarino 2005; McDyre et al 2018) were not increased in both sexes in the HFD-fed rats. This is consistent with a previous report in the DIO SD rat strain (Marques et al 2016).…”

Section: Discussionmentioning

confidence: 89%

The Effect of Diet-induced Obesity on Toxicological Parameters in the Polygenic Sprague-Dawley Rat Model

et al. 2018

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The obese rodent serves as an indispensable tool for proof-of-concept efficacy and mode-of-action pharmacology studies. Yet the utility of this disease model as an adjunct to the conventional healthy animal in the nonclinical safety evaluation of anti-obesity pharmacotherapies has not been elucidated. Regulatory authorities have recommended employing disease models in toxicology studies when necessary. Our study investigated standard and exploratory toxicology parameters in the high-fat diet (HFD)-induced obese, polygenic Sprague-Dawley rat model in comparison to chow diet (CD)-fed controls. We sought to establish feasibility of the model for safety testing and relevance to human obesity pathophysiology. We report that both sexes fed a 45% kcal HFD for 29 weeks developed obesity and metabolic derangements that mimics to a certain extent, common human obesity. Minor clinical pathologies were observed in both sexes and considered related to CD versus HFD differences. Histopathologically, both sexes exhibited mild obesity-associated findings in brown and subcutaneous white fat, bone, kidneys, liver, lung, pancreas, salivary parotid glands, and skeletal muscle. We conclude that chronic HFD feeding in both sexes led to the development of an obese but otherwise healthy rat. Therefore, the diet-induced obese Sprague-Dawley rat may serve as a suitable model for evaluating toxicity findings encountered with anti-obesity compounds.

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Section: Discussionmentioning

confidence: 89%

The Effect of Diet-induced Obesity on Toxicological Parameters in the Polygenic Sprague-Dawley Rat Model

et al. 2018

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“…One way to try to bridge the gap between in vivo and in vitro results is to analyze the genomic response induced by a toxicant, i.e., toxicogenomics. 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 gene module) [13][14][15][16], and that chemical exposures leading to the same injury endpoint cause similar changes in gene expression.…”

Section: Introductionmentioning

confidence: 99%

Concordance between Thioacetamide-Induced Liver Injury in Rat and Human In Vitro Gene Expression Data

Schyman

Printz

Estes

et al. 2020

IJMS

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The immense resources required and the ethical concerns for animal-based toxicological studies have driven the development of in vitro and in silico approaches. Recently, we validated our approach in which the expression of a set of genes is uniquely associated with an organ-injury phenotype (injury module), by using thioacetamide, a known liver toxicant. Here, we sought to explore whether RNA-seq data obtained from human cells (in vitro) treated with thioacetamide-S-oxide (a toxic intermediate metabolite) would correlate across species with the injury responses found in rat cells (in vitro) after exposure to this metabolite as well as in rats exposed to thioacetamide (in vivo). We treated two human cell types with thioacetamide-S-oxide (primary hepatocytes with 0 (vehicle), 0.125 (low dose), or 0.25 (high dose) mM, and renal tubular epithelial cells with 0 (vehicle), 0.25 (low dose), or 1.00 (high dose) mM) and collected RNA-seq data 9 or 24 h after treatment. We found that the liver-injury modules significantly altered in human hepatocytes 24 h after high-dose treatment involved cellular infiltration and bile duct proliferation, which are linked to fibrosis. For high-dose treatments, our modular approach predicted the rat in vivo and in vitro results from human in vitro RNA-seq data with Pearson correlation coefficients of 0.60 and 0.63, respectively, which was not observed for individual genes or KEGG pathways.

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“…For example, chronic treatment with amiodarone, an anti-arrhythmic drug, produces steatosis in patients through impaired mitochondrial function and inhibition of lipid oxidation [13]. Similarly, acute bromobenzene exposure in rats induces steatosis with lipid accumulation in the liver [14]. Indeed, several drugs and environmental chemicals, such as acetaminophen, carbon tetrachloride, and thioacetamide, are in regular use as model liver toxicants to induce a specific liver disease phenotype and understand their pathophysiological mechanisms [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats

Pannala

Estes

Rahim

et al. 2020

IJMS

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Liver disease and disorders associated with aberrant hepatocyte metabolism can be initiated via drug and environmental toxicant exposures. In this study, we tested the hypothesis that gene and metabolic profiling can reveal commonalities in liver response to different toxicants and provide the capability to identify early signatures of acute liver toxicity. We used Sprague Dawley rats and three classical hepatotoxicants: acetaminophen (2 g/kg), bromobenzene (0.4 g/kg), and carbon tetrachloride (0.3 g/kg), to identify early perturbations in liver metabolism after a single acute exposure dose. We measured changes in liver genes and plasma metabolites at two time points (5 and 10 h) and used genome-scale metabolic models to identify commonalities in liver responses across the three toxicants. We found strong correlations for gene and metabolic profiles between the toxicants, indicative of similarities in the liver response to toxicity. We identified several injury-specific pathways in lipid and amino acid metabolism that changed similarly across the three toxicants. Our findings suggest that several plasma metabolites in lipid and amino acid metabolism are strongly associated with the progression of liver toxicity, and as such, could be targeted and clinically assessed for their potential as early predictors of acute liver toxicity.

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Comparative Proteomic Analysis of Liver Steatosis and Fibrosis after Oral Hepatotoxicant Administration in Sprague-Dawley Rats

Cited by 7 publications

References 60 publications

The Effect of Diet-induced Obesity on Toxicological Parameters in the Polygenic Sprague-Dawley Rat Model

The Effect of Diet-induced Obesity on Toxicological Parameters in the Polygenic Sprague-Dawley Rat Model

Concordance between Thioacetamide-Induced Liver Injury in Rat and Human In Vitro Gene Expression Data

Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats

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