Application of toxicogenomics for the risk assessment of the food contaminant acetamide
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ABSTRACT:
PROVIDER: PRJNA549167 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9309260.fastq.gz | Fastqsanger.gz | |||
| SRR9309270.fastq.gz | Fastqsanger.gz | |||
| SRR9309280.fastq.gz | Fastqsanger.gz | |||
| SRR9309290.fastq.gz | Fastqsanger.gz | |||
| SRR9309300.fastq.gz | Fastqsanger.gz |
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Project description:Acetamide (CAS 60-35-5) is detected in common foods including milk, eggs, beef, and roasted coffee beans. Chronic rodent bioassays using high doses (≥1000 mg/kg/day) suggest acetamide is a group 2B possible human carcinogen due to the induction of liver tumors. Weight-of-evidence indicates acetamide is not genotoxic, and therefore a threshold response is expected. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 and 28 days to determine the benchmark dose (BMD), and investigate its mode of action from differential gene expression. Two exposure experiements were carried out in succsession. An initial dose range finding experiment used male Wistar rats gavaged daily for 7 days at 0, 30, 100, 300 and 1000 mg/kd/day. A second experiment used both male and female Wistar rats exposed for 7 and 28 days to 0, 300,500,750,1000 and 1500 mg/kg/day. No treatment related changes in terminal body weight, clinical chemistry, or histopathology were observed at doses of 30, 100, or 300 mkd. At 1000 mkd, the dose reported to elicit carcinogenesis, liver weights decreased 1.3-fold with the presence of single cell necrosis, hepatocyte vacuolization, and increased mitotic activity consistent with a 4.2 fold increase in the cell proliferation index. Accordingly, plasma ALT and AST were increased 2.0- and 2.2-fold, respectively. RNA-Seq analysis identified 1 differentially expressed gene at 300 mkd, and 2,685 at 1000 mkd (|fold-change| ≥ 1.5 and FDR ≤ 0.05). Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Collectively, these results revealed a no-observable adverse effect level (NOAEL) and no-observed-transcriptional effect level (NOTEL) at 300 mkd, warranting further investigation at doses between 300 and 1000 mkd to identify the benchmark dose (BMD). Functional enrichment indicates perturbation of cell cycle and lipid metabolism, though a more refined dose-response evaluation will be needed to demonstrate dose-dependent effects related to the MOA of acetamide. Funding by the Bill and Melinda Gates Foundation (OPP1142801).
2020-01-13 | GSE132815 | GEO
Project description:The application of toxicogenomics as a predictive tool for chemical risk assessment has been under evaluation by the toxicology community for more than a decade. However, toxicogenomics predominately remains a tool for investigative research rather than for regulatory risk assessment. In this study, we aimed to determine whether the current generation of microarray technology in combination with an in vitro experimental design was capable of generating robust, reproducible data of sufficient quality to show promise as a tool for regulatory risk assessment. To this end, we designed a prospective collaborative study to determine the level of inter- and intra-laboratory reproducibility between three independent laboratories. All test sites adopted the same protocols for all aspects of the toxicogenomic experiment including cell culture, chemical exposure, RNA extraction, microarray data generation and analysis. As a case study, the genotoxic carcinogen B[a]P and the human hepatocyte cell line HepG2 were used to generate three comparable toxicogenomic data sets. High levels of technical reproducibility were demonstrated using a widely employed gene expression microarray platform. While differences at the global transcriptome level were still observed between the test sites, a common subset of B[a]P responsive genes was identified across all test sites which included both genes previously reported in the literature as B[a]P responsive in addition to the same most highly up and down regulated genes. Pending further analysis, these preliminary data show promise that the current generation of microarray technology in combination with a standard in vitro experimental design can produce robust data that can be reproducibly generated in independent laboratories. Future work will need to determine whether in vitro model(s) can be not only reproducible but also predictive for a range of toxic chemicals with different mechanisms of action. Such an approach may potentially be part of future in vitro testing regimes for regulatory risk assessment.
2011-12-31 | GSE25936 | GEO
Project description:The application of toxicogenomics as a predictive tool for chemical risk assessment has been under evaluation by the toxicology community for more than a decade. However, toxicogenomics predominately remains a tool for investigative research rather than for regulatory risk assessment. In this study, we aimed to determine whether the current generation of microarray technology in combination with an in vitro experimental design was capable of generating robust, reproducible data of sufficient quality to show promise as a tool for regulatory risk assessment. To this end, we designed a prospective collaborative study to determine the level of inter- and intra-laboratory reproducibility between three independent laboratories. All test sites adopted the same protocols for all aspects of the toxicogenomic experiment including cell culture, chemical exposure, RNA extraction, microarray data generation and analysis. As a case study, the genotoxic carcinogen B[a]P and the human hepatocyte cell line HepG2 were used to generate three comparable toxicogenomic data sets. High levels of technical reproducibility were demonstrated using a widely employed gene expression microarray platform. While differences at the global transcriptome level were still observed between the test sites, a common subset of B[a]P responsive genes was identified across all test sites which included both genes previously reported in the literature as B[a]P responsive in addition to the same most highly up and down regulated genes. Pending further analysis, these preliminary data show promise that the current generation of microarray technology in combination with a standard in vitro experimental design can produce robust data that can be reproducibly generated in independent laboratories. Future work will need to determine whether in vitro model(s) can be not only reproducible but also predictive for a range of toxic chemicals with different mechanisms of action. Such an approach may potentially be part of future in vitro testing regimes for regulatory risk assessment. The aim of this study was to evaluate the inter- and intra-laboratory reproducibility of toxicogenomics data for toxicity testing in a regulatory setting. 3 Test Centres performed the same experimental protocol treating HepG2 cells with 3 mM Benzo[a]pyrene (B[a]P) (in 0.5% DMSO) for 24 hours prior to RNA extraction and microarray analysis. Three biological replicates of B[a]P and DMSO treatments were analysed by microarray analysis in each Test Centre. Two Test Centres analysed one sample in triplicate to determine technical reproducibility of the chosen array platform. One Centre analysed two samples in duplicate. 24 samples in total were used in this study
2011-12-31 | E-GEOD-25936 | biostudies-arrayexpress
Project description:Toxic compounds such as organochlorine pesticides (OCs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ether flame retardants (PBDEs) have been detected in fish, birds, and aquatic mammals that live in the Columbia River or use the river as a food source. We developed a custom microarray for largescale suckers (Catostomus macrocheilus) and used it to investigate the molecular effects of contaminant exposure on wild fish in the Columbia River. Using Significance Analysis of Microarrays (SAM) we identified 72 probes representing 69 unique genes with expression patterns that correlated with hepatic tissue levels of OCs, PCBs, or PBDEs. These genes were involved in many biological processes previously shown to respond to contaminant exposure, including drug and lipid metabolism, apoptosis, cellular transport, oxidative stress, and cellular chaperone function. The relation between gene expression and contaminant burden suggests that these genes may respond to environmental contaminant exposure and are promising candidates for further field and laboratory studies to develop biomarkers for monitoring exposure of wild fish to contaminant mixtures found in the Columbia River Basin
2013-12-04 | GSE41016 | GEO
Project description:We tested the hypothesis that BHT is an endocrine disruptor by using a Next Generation Risk Assessment (NGRA) method. Four different cell lines: A549, HCC1428, HepG2 and MCF7 were treated with BHT and a series of BHT analogs at 5 different concentrations, RNA was isolated from cell extracts and run on the L1000 gene array platform. A toxicogenomics-based assessment was performed by comparing BHT’s unique genomic signature to a large external database containing signatures of other compounds (including many known endocrine disruptors) to identify if any endocrine disruption-related modes of action (MoAs) are prevalent among BHT and other compounds with similar genomic signatures. In addition, we performed a toxicogenomics-based structure activity relationship (SAR) assessment of BHT and a series of structurally similar analogues to understand if endocrine disruption is a relevant MoA for chemicals that are considered suitable analogs to BHT using the P&G read across framework (Wu et al., 2010). The platform is GPL20573: Broad Institute Human L1000 epsilon http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL20573
2022-10-17 | GSE211553 | GEO
Project description:Due to its high throughput nature, toxicogenomics can provide a broad picture of a toxic response, offering the ideal functional platform for grouping chemicals according to mechanistic similarity. In this way, toxicogenomics has found its way into predictive toxicology. However, so far, the predictive potential of toxicogenomics in an endocrine disruptive screening context has not been extensively examined. The aim of this study was to combine a toxicogenomics approach with an estrogen-sensitive MCF-7 cell system. In total, 18 compounds with endocrine disruptive potential were selected, of which 11 are listed as ICCVAM reference compounds for validation of estrogen receptor (ER) binding and transactivation assays. In this way, the grouping and classification potential of the gene expression profiles could be directly compared to the more classical estrogenicity screens, such as ER binding, ER transactivation and MCF-7 cell proliferation assays. Results indicated that this toxicogenomics approach was clearly capable of grouping compounds into strong, weak and non estrogenic groups. This demonstrates the value of toxicogenomics for evaluating gradual differences in related modes of action, in addition to the more common search for opposite modes of action. The chemical groups were represented by interesting marker genes such as PGR, ERBB2, CXCL12, AREG and EGR3, including some early-responsive (4h) potential biomarkers. These results open the discussion on the added value of a broader endpoint evaluation in estrogenicity screens provided by omics-techniques compared to the classical single endpoint based assays.
2015-10-01 | GSE16881 | GEO
Project description:Toxic compounds such as organochlorine pesticides (OCs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ether flame retardants (PBDEs) have been detected in fish, birds, and aquatic mammals that live in the Columbia River or use the river as a food source. We developed a custom microarray for largescale suckers (Catostomus macrocheilus) and used it to investigate the molecular effects of contaminant exposure on wild fish in the Columbia River. Using Significance Analysis of Microarrays (SAM) we identified 72 probes representing 69 unique genes with expression patterns that correlated with hepatic tissue levels of OCs, PCBs, or PBDEs. These genes were involved in many biological processes previously shown to respond to contaminant exposure, including drug and lipid metabolism, apoptosis, cellular transport, oxidative stress, and cellular chaperone function. The relation between gene expression and contaminant burden suggests that these genes may respond to environmental contaminant exposure and are promising candidates for further field and laboratory studies to develop biomarkers for monitoring exposure of wild fish to contaminant mixtures found in the Columbia River Basin Correlation between contaminant exposure and gene expression profiles of wild largescale suckers collected from three different sites in the Columbia River. At each site, liver samples of six to eight different fish were analyzed using microarrays.
2013-12-04 | E-GEOD-41016 | biostudies-arrayexpress
Project description:In vitro toxicogenomics signatures to predict mode of action can facilitate chemical screening. We recently demonstrated the use of the TGx-28.65 genomic biomarker (representing: toxicogenomics (TGx), developed using a 28 chemical training set, and comprising 65 genes) in classifying agents as genotoxic (DNA damaging) and non-genotoxic in human lymphoblastoid TK6 cells. Because TK6 cells do not possess cytochrome P450 activity, we confirmed accurate classification in cells co-exposed to 1% 5,6 benzoflavone/phenobarbital-induced rat liver S9 for metabolic activation. However, chemicals may require different types of S9 for activation. Here we conducted experiments in TK6 cells exposed to chemicals in the presence of 2% or 10% Aroclor-induced, or 5% ethanol-induced rat liver S9 to expand TGx-28.65 biomarker application. Gene expression profiles were produced 3-4 hr following a 4 hr co-exposure of TK cells to test chemicals (seven genotoxic and two non-genotoxic, three concentrations, and concurrent solvent controls) and S9. Relative survival and micronucleus frequency was assessed by flow cytometry in cells 20 hr after the exposure. We found that genotoxicity/non-genotoxicity could be accurately predicted for the test compounds using the different S9s. One technical replicate of cells co-treated with dexamethasone and 10% Aroclor-induced S9 was falsely predicted as genotoxic, suggesting caution in using high concentrations of S9. TGx-28.65 correctly classified low concentrations of genotoxic chemicals (those not causing cytotoxicity or micronuclei) as genotoxic, demonstrating that it is a sensitive biomarker of genotoxicity. Overall, the work confirms that different S9s can be used in TK6 cells without impairing predictivity using the TGx-28.65 biomarker.
2016-08-25 | GSE74216 | GEO
Project description:Acetamide (CAS 60-35-5) is detected in common foods. Chronic rodent bioassays led to its classification as a group 2B possible human carcinogen due to the induction of liver tumors in rats. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 or 28 days at doses of 300 to 1500 mg/kg/day (mkd) to determine a point of departure (POD) and investigate its mode of action (MoA). Ki67 labeling was increased at doses ≥750 mkd up to 3.3-fold representing the most sensitive apical endpoint. Differential gene expression analysis by RNA-Seq identified 1110 and 1814 differentially expressed genes in male and female rats, respectively, following 28 days of treatment. Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Benchmark dose (BMD) modeling of the Ki67 labeling index determined the BMD10 lower confidence limit (BMDL10) as 190 mkd. Transcriptional BMD modeling revealed excellent concordance between transcriptional POD and apical endpoints. Collectively, these results indicate that acetamide is most likely acting through a mitogenic MoA, though specific key initiating molecular events could not be elucidated. A POD value of 190 mkd determined for cell proliferation is suggested for risk assessment purposes.
| S-EPMC7014822 | biostudies-literature
Project description:In this study we performed microarray-based molecular profiling of liver samples from Wistar rats exposed to genotoxic carcinogens (GC), nongenotoxic carcinogens (NGC) or non-hepatocarcinogens (NC) for up to 14 days. In contrast to previous toxicogenomics studies aimed at the inference of molecular signatures for assessing the potential and mode of compound carcinogenicity, we considered multi-level omics data. Besides evaluating the predictive power of signatures observed on individual biological levels, such as mRNA, miRNA and protein expression, we also introduced novel feature representations which capture putative molecular interactions or pathway alterations by integrating expression profiles across platforms interrogating different biological levels. Male Wistar rats were treated by oral gavage with the eight nongenotoxic hepatocarcinogens Phenobarbital sodium (PB), Piperonylbutoxide (PBO), Dehydroepiandrosterone (DHEA), Acetamide (AA), Methapyrilene HCl (MPy), Methylcarbamate (Mcarb), Diethylstilbestrol (DES) and Ethionine (ETH), the two genotoxic carcinogens C.I Direct Black (CIDB) and dimethylnitrosamine (DMN), the two non-hepatocarcinogens Cefuroxime (CFX) and Nifedipine (Nif), and the three compounds with undefined carcinogenic class Cyproterone acetate (CPA), Thioacetamid (TAA) and Wy-14643 (Wy). Depending on the administered compound, livers were taken after 3, 7, or 14 days for histopathological evaluation. From the five animals per treatment group three animals were selected based on the histopathological findings and subjected to molecular profiling using Affymetrix RG-230A arrays (mRNA expression), Agilent G4473A arrays (miRNA expression) and Zeptosens ZeptoMARK reverse arrays (protein expression).
2014-08-18 | E-GEOD-53083 | biostudies-arrayexpress