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A quantitative proteomic based approach for identifying and characterizing APAP-induced liver perturbation in zebrafish (Danio rerio)

ABSTRACT: The relative quantification of sex-specific proteomic responses led to the detection of potential biomarkers for hepatotoxicity and as well as the identification of the underlying molecular perturbation needed to unravel the impact of APAP-induced liver injury on physiological system.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Danio Rerio (zebrafish) (brachydanio Rerio)

TISSUE(S): Testis, Liver, Oocyte

SUBMITTER: Steve Ayobahan

LAB HEAD: Dr. Elke Eilebrecht

PROVIDER: PXD013357 | Pride | 2019-11-18

REPOSITORIES: Pride

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Detection of biomarkers to differentiate endocrine disruption from hepatotoxicity in zebrafish (Danio rerio) using proteomics.

Ayobahan Steve U SU Eilebrecht Sebastian S Baumann Lisa L Teigeler Matthias M Hollert Henner H Kalkhof Stefan S Eilebrecht Elke E Schäfers Christoph C

Chemosphere 20190925

Measurement of specific biomarkers identified by proteomics provides a potential alternative method for risk assessment, which is required to discriminate between hepatotoxicity and endocrine disruption. In this study, adult zebrafish (Danio rerio) were exposed to the hepatotoxic substance acetaminophen (APAP) for 21 days, in a fish short-term reproduction assay (FSTRA). The molecular changes induced by APAP exposure were studied in liver and gonads by applying a previously developed combined FS ...[more]

PMID: 31726584

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A quantitative proteomics-approach to detect impaired estrogen synthesis in zebrafish (Danio rerio)

Project description:Identification and relative quantification of proteins associated with substance specific alterations and sex-specific physiological responses following aromatase inhibition.

2019-04-30 | PXD011022 | Pride

Hepatic responses of mice and rats to equivalent acetaminophen (APAP) insult – SWATH proteomics

Project description:The well-known difference in sensitivity of mice and rats to acetaminophen (APAP) liver injury has been related to differences in the fraction that is bioactivated to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Physiologically-based pharmacokinetic modelling was used to identify doses of APAP (300 and 1000 mg/kg in mice and rats, respectively) yielding similar hepatic burdens of NAPQI, to enable the comparison of temporal liver tissue responses under conditions of equivalent chemical insult.

2023-08-31 | PXD034438 | Pride

Transcription profiling of mouse liver after Acetaminophen intoxication

Project description:Acetaminophen (APAP) is the most widely used analgesic in the United States. Its acute overdose causes liver damage by inducing localized centrilobular cell death. Because of widespread use, APAP toxicity has become the most frequent cause of acute liver failure. Many factors have been associated with the susceptibility of APAP-induced liver injuries, however, few of them have been confirmed and used in the clinical setting. We tried to identify the subset of factors that could affect susceptibility to APAP-induced liver injury by an integrative genetic, transcriptional and 2-D-NMR-based metabolomic analysis across a panel of inbred mouse strains. Experiment Overall Design: After a single administration of high dose (300 mg/kg i.p.) APAP, liver and blood samples were extracted from 3 sensitive (C57B6, DBA/2, and SmJ) and 1 resistant (SJL) mice strains at 0, 3 and 6 hour after APAP exposure. Endogenous metabolites from liver samples were analyzed by 1H-13C 2-dimensional-NMR and gene expression changes occurring within these liver samples were simultaneously analyzed using Affymetrix microarrays. The transcriptional and metabolomic data was jointly analyzed, and functional information within the Gene Ontology database was used to identify the subset of genes that could affect susceptibility to APAP-induced liver injury in the early phase response.

2009-08-23 | E-GEOD-17649 | biostudies-arrayexpress

Proteomics Indicates Lactate Dehydrogenase is Prognostic in Acetaminophen-induced Acute Liver Failure Patients and Reveals a Role for LKB1-AMPK Signaling

Project description:Better biomarkers to predict death early in acute liver failure (ALF) are needed. To that end, we obtained early (study day 1) and later (day 3) serum samples from transplant-free survivors (n=28) and non-survivors (n=30) of acetaminophen (APAP)-induced ALF from the NIH-sponsored Acute Liver Failure Study Group, and from control volunteers (n=10). To identify proteins that increase early in serum during ALF, we selected individuals from this cohort for whom ALT was lower on day 1 than day 3, indicating a time point before the peak of injury (n=10/group). We then performed untargeted proteomics on their day 1 samples. Out of 1,682 quantifiable proteins, 79 were elevated ≥4-fold in ALF patients vs. controls and 23 of those were further elevated ≥4-fold in non-survivors vs. survivors, indicating potential to predict death. Interestingly, the biomarker with best performance was LDH. To confirm the prognostic potential of LDH, we measured activity in all day 1 and 3 samples from all 58 ALF patients. LDH was elevated in the non-survivors vs. survivors on both days. In addition, receiver operating characteristic (ROC) curve analyses revealed that LDH alone performed similarly to the model for end-stage liver disease (MELD), while a combination of MELD and LDH outperformed either alone. Finally, Upstream Analysis of our proteomics data indicated activation of LKB1-AMPK signaling in liver regeneration after APAP overdose and we confirmed that in mice. Overall, we conclude LDH can predict death in APAP-induced ALF and that LKB1-AMPK signaling may be a promising therapeutic target to improve survival.

2022-08-12 | PXD029576 | Pride

Shifted Metabolic Bias in Livers of Mice Lacking Hepatocytic Thioredoxin Reductase-1 Protects Against Acetaminophen Toxicity

Project description:Genetic disruption of thioredoxin reductase 1 protects against acetaminophen (APAP) toxicity. To determine the role of the thioredoxin system on xenobiotic metabolism we challeneged wildtype and txnrd1liver-null mice with acetaminophen. Adult male wildtype and txnrd1 liver-null mice (C57BL6/J) were treated with either saline (PBS) or 100mg/kg APAP. Liver RNA was harvested eight hours after challenge and processed for microarray analysis. Comparison of 2 treatment conditions in 2 genotypes, biological replicates in triplicate.

2013-06-08 | E-GEOD-37874 | biostudies-arrayexpress

Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury

Project description:Molecular profiling of infiltrating monocyte-derived macrophages versus resident kupffer cells following acute liver injury The liver has a remarkable capacity to regenerate after injury; yet, the role of macrophages (MF) in this process remains controversial mainly due to difficulties in distinguishing between different MF-subsets. Here, we utilized a murine model of acute liver injury caused by overdose of acetaminophen (APAP) and defined three distinct MF subsets that populate the liver following injury. Accordingly, resident Kupffer cells (KC) were significantly reduced upon APAP-challenge and started recovering by self-renewal at resolution phase without contribution of circulating Ly6Chi monocytes. The latter were recruited in a CCR2 and M-CSF mediated pathway at the necro-inflammatory phase and differentiated into ephemeral Ly6Clo MF subset at resolution phase. Moreover, their inducible ablation resulted in impaired recovery. Microarray based molecular profiling uncovered high similarity between steady state KC and those recovered at the resolution phase. In contrast, KC and monocyte-derived MF displayed distinct pro-restorative genetic signature at the resolution phase. Finally, we show that infiltrating monocytes acquire a pro-restorative polarization manifested by unique expression of pro-angiogenesis mediators and genes involved with inhibition of neutrophil activity and recruitment and promotion of their clearance. Collectively, our results present a novel phenotypic, ontogenic and molecular definition of liver-MF compartment following acute injury. 11 Samples (arrays) were performed. We generated pairwise comparison between all the different macrophages stages, using Partek Genomics Suite. Genes with p?5%[FDR] and a fold-change difference of ?2 or <-2 were selected.

2014-08-01 | E-GEOD-55606 | biostudies-arrayexpress

Protein Targets of Acetaminophen Covalent Binding in Rat and Mouse Liver Studied by LC-MS/MS

Project description:Acetaminophen (N-acetyl-p-aminophenol; APAP) is a mild analgesic and antipyretic used commonly worldwide. Although APAP is considered a safe and effective over-the-counter medication, it is also the leading cause of drug-induced acute liver failure. Its hepatotoxicity has been linked to the covalent binding of its reactive metabolite, N-acetyl p-benzoquinone imine (NAPQI), to proteins. The aim of this in vivo study was to identify APAP-protein targets in both rat and mouse liver, and to compare the results from both species, using bottom-up proteomics and targeted multiple reaction monitoring (MRM) experiments. Livers from rats and mice, treated with APAP, were homogenized and digested by trypsin. Digests were then fractionated by mixed-mode solid-phase extraction prior to liquid chromatography-tandem mass spectrometry (LC-MS/MS) using scheduled multiple reaction monitoring (MRM) acquisition. The targeted assays were optimized based on high-resolution MS/MS data from information-dependent acquisition (IDA) using control liver homogenates treated with a custom alkylating reagent forming a positional isomer of the APAP modification on all cysteine residues, in order to build an in-house modified peptide database for targeted analysis. A list of putative in vivo targets of APAP were screened from previous in vitro studies, data-dependent high-resolution MS/MS analyses of liver digests, as well as selected proteins from the target protein database (TPDB), an online resource which references previous reports of proteins found to be modified by acetaminophen. Multiple protein targets of APAP in each species were found, while confirming modification sites.

2022-02-17 | PXD027674 | Pride

Discover preclinical biomarkers of hepatotoxicity: Acetaminophen and Carbon tetrachloride

Project description:Preclinical biomarkers useful for identification of idiosyncratic drugs have not been identified. It is hypothesized that patterns of transcript expression for the hepatotoxicants, including classical and idiosyncratic hepatotoxicants, are similar and the patterns differ from those of non-hepatotoxicants. This experiment is part of the biomarkers study, and focus on two clasical hepatotoxicants: Acetaminophen and Carbon tetrachloride. We have employed whole genome microarray expression profiling to identify liver gene expression changes induced by hepatotoxicants. For the same animal, urinary microRNA profiling were analyzed. APAP and CCl4 both significantly increased the urinary levels of 44 and 28 miRNAs, respectively. In addition, 10 of the increased miRNAs were in common between APAP and CCl4. Computational analysis was used to predict target genes of the 10 shared hepatotoxicant-induced miRNAs. From the same animals, liver gene expression profiling was performed using whole genome microarrays. Eight putative target genes were found to be significantly altered in the liver of APAP and CCl4 treated animals. Acetaminophen induced liver gene expression changes in rats (Six to seven week-old male Sprague-Dawley rats, provided by the US Food and Drug Administration National Center for Toxicological Research (NCTR) breeding colonies, were used for the study.) were measured at 6 hours, 24 hours, 3 days and 7 days after exposure to doses of 0, 100 and 1250 mg/kg. Carbon tetrachloride induced liver gene expression changes in rats were measured at 6 hours, 24 hours and 3 days after exposure to doses of 0, 50 and 2000 mg/kg. Each group has at least 4 animals, total of 96 samples.

2012-03-15 | E-GEOD-32891 | biostudies-arrayexpress

Atlantic salmon liver transcriptome response to exposure to three human pharmaceuticals

Project description:The combination of increasing consumption rates and limited elimination under conventional waste water treatment practices of many pharmaceutical compounds has now led to their detection in aquatic environments. Three of the most frequently detected pharmaceuticals in the environment are Acetaminophen (APAP), Atenolol (AT) and Carbamazepine (CBZ). Atlantic salmon (parr) was exposed to environmentally relevant levels of Acetaminophen (APAP) (54.77 ± 34.67 µg·L-1), Atenolol (AT) (11.08 ± 7.98 µg·L-1) and Carbamzepine (CBZ) (7.85 ± 0.13 µg·L-1). Gene expression was analyzed in liver tissues using a 16K GRASP (University of Victoria, Canada) cDNA microarray. GRASP 16K v.2 cDNA microarrays were used for this study (Accession # A-GEOD-2716). A dual-labelled experimental design was employed for the microarray hybridisations. Each experimental cDNA sample (Cy3 labeled) was competitively hybridised against a common pooled-reference sample (Cy5 labeled). The entire experiment comprised 20 hybridisations - 4 states (APAP, AT, CBZ, control) × 1 time-point ( at 5 days) × 5 biological replicates (males only). Hybridisations were undertaken concurrently.

2012-02-29 | E-TABM-1213 | biostudies-arrayexpress

Differential Regulation of Mitogen-Activated Protein Kinases by Acetaminophen in TAMH cells

Project description:Acetaminophen (APAP), a widely used analgesic and antipyretic that is considered to be relatively safe at recommended doses, is the leading cause of drug-induced liver failure in the United States. 3M-bM-^@M-^Y-Hydroxyacetanilide (AMAP), a regioisomer of acetaminophen is useful as a comparative tool for studying APAP-induced toxicity since it is non-toxic relative to APAP. TGF-alpha transgenic mouse hepatocytes were treated with both isomers to investigate mitogen-activated protein kinase cascades in order to differentiate their toxicological outcomes. Mitogen-activated protein kinase (MAPK) cascade expression and activation were measured using microarray and Bioplex technologies, respectively. APAP treatment led to c-Jun N-terminal kinase (JNK) activation, whereas AMAP treatment led to the activation of extracellular-signal-regulated protein kinase (ERK). The microarray data suggested APAP treatment may upregulate gene expression at multiple levels of the JNK cascade including a JNK-related scaffold protein. Expression data was related to phosphoprotein levels using the Bioplex system. APAP treatment led to a significant activation of JNK compared to its regioisomer. In contrast, microarray analysis of AMAP showed a slight upregulation of ERK gene activity. Furthermore, Bioplex data showed AMAP treatment led to significant ERK phosphorylation compared to APAP. Cell viability assays confirmed that APAP-induced activation of JNK was related to higher rates of cell death, whereas activation of ERK by AMAP may be cytoprotective. 27 arrays, 9 experimental groups, 2hr AMAP, 2hr APAP, 2hr Control, 6hr AMAP, 6hr APAP, 6hr Control, 24hr AMAP, 24hr APAP, 24hr Control.

2010-07-06 | E-GEOD-18614 | biostudies-arrayexpress

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