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

ABSTRACT: 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.

SUBMITTER: Te JA

PROVIDER: S-EPMC5064727 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Te Jerez A JA AbdulHameed Mohamed Diwan M MD Wallqvist Anders A

Journal of applied toxicology : JAT 20160104 9

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 Eva ...[more]

PMID: 26725466

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Project description:An increasing number of cases of herb-induced liver injury (HILI) have been reported, presenting new clinical challenges. In this study, taking Polygonum multiflorum Thunb (PmT) as an example, we proposed a computational systems toxicology approach to explore the molecular mechanisms of HILI. First, the chemical components of PmT were extracted from 3 main TCM databases as well as the literature related to natural products. Then, the known targets were collected through data integration, and the potential compound-target interactions (CTIs) were predicted using our substructure-drug-target network-based inference (SDTNBI) method. After screening for hepatotoxicity-related genes by assessing the symptoms of HILI, a compound-target interaction network was constructed. A scoring function, namely, Ascore, was developed to estimate the toxicity of chemicals in the liver. We conducted network analysis to determine the possible mechanisms of the biphasic effects using the analysis tools, including BiNGO, pathway enrichment, organ distribution analysis and predictions of interactions with CYP450 enzymes. Among the chemical components of PmT, 54 components with good intestinal absorption were used for analysis, and 2939 CTIs were obtained. After analyzing the mRNA expression data in the BioGPS database, 1599 CTIs and 125 targets related to liver diseases were identified. In the top 15 compounds, seven with Ascore values >3000 (emodin, quercetin, apigenin, resveratrol, gallic acid, kaempferol and luteolin) were obviously associated with hepatotoxicity. The results from the pathway enrichment analysis suggest that multiple interactions between apoptosis and metabolism may underlie PmT-induced liver injury. Many of the pathways have been verified in specific compounds, such as glutathione metabolism, cytochrome P450 metabolism, and the p53 pathway, among others. Hepatitis symptoms, the perturbation of nine bile acids and yellow or tawny urine also had corresponding pathways, justifying our method. In conclusion, this computational systems toxicology method reveals possible toxic components and could be very helpful for understanding the mechanisms of HILI. In this way, the method might also facilitate the identification of novel hepatotoxic herbs.

Project description:BackgroundThe bacterial endotoxin lipopolysaccharide (LPS) was the classic inducer to establish many inflammatory disease models, especially multiple organ injury. Evidences indicated that the mechanism that causes inflammation response is not just related to cytokine release. The main aim of this study was to better elucidate the possible links between metabolic changes and the pathogenesis of LPS-induced acute liver and kidney in order to understand the mechanisms and screening therapeutic targets for developing early diagnostic strategies and treatments.MethodsAn experimental rat model was established by intraperitoneal injection of 10 mg/kg LPS. An untargeted metabolomics analysis of the serum in the LPS and control groups was carried out using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/QTOF-MS). LPS-induced pathological damage in the lungs, liver, kidneys, and colon was observed, along with changes in biochemical indexes, indicating that there was a severe inflammatory response in many organs after administration of LPS for 8 h. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) showed distinct separation in the serum metabolite profiles between the LPS and control groups, indicating significant changes in endogenous metabolites.ResultsThe untargeted metabolomics analysis showed that there were 127 significantly different serum metabolites and 53 altered pathways after LPS administration, including pathways related to the metabolism of D-glutamine and D-glutamate, taurine and hypotaurine, beta-alanine, glutathione, and butanoate, which are involved in the inflammatory response, oxidative stress, and amino acid metabolism.ConclusionThe study suggested that LPS-induced acute liver and kidney injury mainly involves inflammatory response, oxidative stress, and protein synthesis, finally causing multi-organ damage. Correcting the disturbances to the metabolites and metabolic pathways may help to prevent and/or treat LPS-induced acute liver and kidney damage.

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

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

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