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Discover preclinical biomarkers of hepatotoxicity: Acetaminophen and Carbon tetrachloride

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE32891 | GEO | 2012/03/15

SECONDARY ACCESSION(S): PRJNA146629

REPOSITORIES: GEO

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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

MicroRNA-SEQ analysis of kidney and liver damage in rat

Project description:Purpose : Identification of novel microRNA biomarkers in urine and plasma from rats with kidney or liver damage micoRNA-SEQ was used to analyze changes in miRNA profiles of tissue, plasma and urine samples of rats treated with either a nephrotoxicant (cisplatin) or one of two hepatotoxicants (Acetaminophen [APAP] or Carbon Tetrachloride [CCL4]).

2016-06-01 | E-GEOD-79017 | biostudies-arrayexpress

Carbon tetrachloride (CCl4) induced liver fibrosis

Project description:To understand the fibrotic response in the CCl4 induced liver fibrosis model, we performed RNA-seq of liver samples from mice treated with oil or CCl4.

2022-08-19 | GSE207855 | GEO

Circulating miRNAs of acetaminophen-overdosed patients

Project description:Drug-induced liver injury (DILI) is a leading cause of acute liver failure and the major reason for withdrawal of drugs from the market. Preclinical evaluation of drug candidates has failed to detect about 40% of potentially hepatotoxic compounds in humans. At the onset of liver injury in humans, currently used biomarkers have difficulty differentiating severe DILI from mild, and/or predict the outcome of injury for individual subjects. Therefore, new biomarker approaches for predicting and diagnosing DILI in humans are urgently needed. Recently, circulating microRNAs (miRNAs) such as miR-122 and miR-192 have emerged as promising biomarkers of liver injury in preclinical species and in DILI patients. In this study, we focused on examining global circulating miRNA profiles in serum samples from subjects with liver injury caused by accidental acetaminophen (APAP) overdose. Upon applying next generation high-throughput sequencing of small RNA libraries, we identified 36 miRNAs, including 3 novel miRNA-like small nuclear RNAs, which were enriched in the serum of APAP overdosed subjects. The set comprised miRNAs that are functionally associated with liver-specific biological processes and relevant to APAP toxic mechanisms. Although more patients need to be investigated, our study suggests that profiles of circulating miRNAs in human serum might provide additional biomarker candidates and possibly mechanistic information relevant to liver injury.

2014-11-28 | GSE59565 | GEO

Early microRNA responses in rodent liver mediated by furan exposure establish dose thresholds for later adverse outcomes

Project description:In this study, we evaluated the utility of microRNA (miRNA) profiling in female B6C3F1 mouse liver to indicate mechanisms of liver perturbation due to short-term exposure of the known rodent liver hepatotoxicant and carcinogen, furan. Analyses indicated a robust dose response for 34 miRNAs to furan and involvement of p53-linked pathways in furan-mediated hepatotoxicity. Overall, these results indicate mechanistic involvement of miRNA in furan carcinogenicity and provide evidence of their potential utility as accessible biomarkers of exposure and disease.

2023-09-05 | GSE224206 | GEO

Acute and chronic liver injury change the small RNA cargoes carried by serum small extracellular vesicles in mice

Project description:Compared to whole serum miRNAs, miRNAs in serum small extracellular vesicles (sEVs) are well protected form RNA enzymes, thus provide a consistent source of miRNA for disease biomarker detection. Serum sEVs and their miRNA cargos released by injured liver cells could be promising biomarkers for diagnosis of liver diseases. We were very interested to find out the effects of liver injury on serum extracellular vesicles as well as the small RNA components they transported, if there is any difference between acute and chronic injury. Study in this regard will help us to identify new serum biomarkers for liver injury, and to find out if there are specific markers for acute or chronic liver injury. To identify potential biomarker for liver injury based on serum sEVs miRNAs, we established the carbon tetrachloride (CCL4) induced acute and chronic liver injury mice model, and examined the dynamic changes of small RNA components, especially miRNAs, in serum sEVs.

2021-08-07 | E-MTAB-9462 | biostudies-arrayexpress

Gene expression profile of liver tissue from carbon tetrachloride (CCl4)-treated mouse cultured ex vivo

Project description:Gene-expression profiles of liver tissue of cabon tetrachloride (CCl4)-treated and control mice were obtained before and after organotypic ex vivo tissue culture. keywords: liver tissue, mouse, gene-expression microarray, Illumina, ex vivo tissue culture

2016-12-16 | GSE71379 | GEO

The zebrafish embryo as an alternative model for the evaluation of liver toxicity using histopathology and expression profiling

Project description:The zebrafish is as a powerful vertebrate model system for modeling human disease including liver pathology. In ZFE, hepatic responses can be expected after exposure to hepatotoxicants, because hepatocytes are present from 36-hpf and at 72-hpf the liver is fully functioning. These characteristics make the whole ZFE an attractive alternative model for compound-induced hepatotoxicity screening. Therefore, the main objective of this study is to further strengthen the applicability of whole ZFE as an alternative model for hepatotoxicity testing, with a special focus on the ability to identify gene expression responses in whole ZFE that are suggestive of hepatotoxicity. Deep sequence technology is applied to assess whether hepatotoxicity-specific transcripts that are identified in livers of hepatotoxicant treated adult zebrafish can be detected in whole ZFE as well. Whole zebrafish embryo and adult zebrafish are exposed for 48 hours to human hepatotoxicants. Afterwards, the adult liver is dissected and snap frozen untill processed for RNA isolation. The whole zebrafish embryos are pooled, one sample consists of 15 embryos, and are also snap frozen untill processed for RNA isolation. For every sample RNA is isolated according to the protocol of de Jong et al (2009). and then equal amounts of every sample is pooled. The two pools (one for the adult zebrafish liver, the other for the whole zebrafish embryo) are sequenced.

2015-05-15 | E-GEOD-38042 | biostudies-arrayexpress

Next Generation Sequencing (NGS) Facilitates Quantitative Analysis of Differentially Expressed Genes in Liver Regeneration After Combined Treatment With Ethanol And Carbon Tetrachloride

Project description:Purpose: The goals of this study are to use NGS-derived liver transcriptome profiling (RNA-seq) and identify differentially expressed genes in regenerating livers that were treated with ethanol and carbon tetrachloride. Methods: Liver mRNA profiles were generated from ethanol/CCl4-treated floxed homozytoes and Ctgf conditional knockout mice by deep sequencing, in duplicate, using Illumina GAIIx. qRT–PCR validation was performed using SYBR Green assay. Results: Ctgf deficiency was associated with 220 downregulated genes and 29 upregulated genes whereas Yap1 null livers had 351 downregulated genes and 287 upregulated genes after ethanol/CCl4 induced liver damage Conclusions: This study provides detailed analysis of liver transcriptomes in absence of Ctgf or Yap1 genes during ethanol/CCl4-induced injury, with biologic replicates, generated by RNA-seq technology.

2020-12-03 | GSE123309 | GEO

The zebrafish embryo as an alternative model for the evaluation of liver toxicity using histopathology and expression profiling

2015-05-15 | GSE38042 | GEO

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