Transcriptional profiling of microRNAs after short-term exposure of CD1-mice to carcinogenic and non-carcinogenic chemicals
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE67943 | GEO | 2018/04/13
REPOSITORIES: GEO
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Project description:Assessing the carcinogenic potential of drug candidates is a costly procedure which requires the life-long treatment of rodents at different dose levels. A promising approach, which may to a certain degree reduce the need for animal studies in the future is toxicogenomics. The idea is to employ microarray platforms for the genome-wide expression profiling of compounds, which may facilitate the discovery of biomarker genes and provide insights in molecular mechanisms. We profiled global mRNA expression in the liver of male and female CD-1 mice treated with genotoxic, nongenotoxic, and non-hepatocarcinogenic compounds up to two weeks.
2013-09-11 | GSE44783 | GEO
Project description:Assessing the carcinogenic potential of drug candidates is a costly procedure which requires the life-long treatment of rodents at different dose levels. A promising approach, which may to a certain degree reduce the need for animal studies in the future is toxicogenomics. The idea is to employ microarray platforms for the genome-wide expression profiling of compounds, which may facilitate the discovery of biomarker genes and provide insights in molecular mechanisms. We profiled global mRNA expression in the liver of male and female CD-1 mice treated with genotoxic, nongenotoxic, and non-hepatocarcinogenic compounds up to two weeks. Diverse compounds were administrated to male and female mice CD-1 mice by oral gavage up to 14 days. In order to chose appropriate dose levels for the carcinogenic substances, the dose reported to be carcinogenic in the 2-year mouse bioassay as stated in the CPDB database (http://potency.berkeley.edu/) was used. To ensure clearly visible changes in gene expression in response to treatment with non-hepatocarcinogens, a high dose was used for these compounds. After 3 and 14 days of treatment, respectively, the animals were anesthetized using isoflurane, exsanguinated from the heart and then subjected to necropsy. The median lobe and left lateral liver lobe were cut in cubes with 4-5 mm side length, placed in Wheaton Cryovials, snap frozen in liquid nitrogen and kept at -80°C until extraction.
2013-09-11 | E-GEOD-44783 | biostudies-arrayexpress
Project description:The human body is continuously exposed to various compounds that could initiate or accelerate cancer development. Such carcinogenic compounds can be classified into a genotoxic and non-genotoxic group. Especially carcinogenicity of non-genotoxic compounds is difficult to determine with current in vitro assessments and therefore has to be improved urgently. Here, we used a toxicogenomics-based approach by genome-wide microRNA expression profiling of mouse embryonic stem (mES) cells to identify microRNA classifiers for genotoxic carcinogens (GTXC), non-genotoxic carcinogens (NGTXC) and oxidative (Ox) compounds. We exposed mES cells to four different NGTXC, four GTXC and four Ox compounds. Differential microRNA expression was determined 4, 8 and 12 hours after exposure and was used to assess its discriminative power for NGTXC and GTXC. We generated an accurate classifier set, which was discriminative for NGTXC using a tiered approach. In conclusion, our study indicates that microRNA expression profiles can discriminate between NGTXC, GTXC and Ox compounds with high accuracy.
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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).
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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).
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Project description:The purpose of the study was to investigate the nongenotoxic carcinogenic effect of Pioglitazone. Pioglitazone is a PPARgamma agonist and is known to cause bladder tumours in male rats and an increase in the incidence of bladder cancer in humans has been observed in patients treated with Pioglitazone. Pioglitazone is not considered genotoxic or carcinogenic in mice and tumours are only observed in male rats suggesting a nongenotoxic mechanism of tumorigenesis. A suggested hypothesis is urinary calculi formation and subsequent irritation, hyperplasia and metaplasia. Rosiglitazone was used as reference compound as this PPARgamma agonist does not cause changes in the bladder but cause lipoma/liposarcoma in rats.
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Project description:The purpose of the study was to investigate the nongenotoxic carcinogenic effect of Pioglitazone. Pioglitazone is a PPARgamma agonist and is known to cause bladder tumours in male rats and an increase in the incidence of bladder cancer in humans has been observed in patients treated with Pioglitazone. Pioglitazone is not considered genotoxic or carcinogenic in mice and tumours are only observed in male rats suggesting a nongenotoxic mechanism of tumorigenesis. A suggested hypothesis is urinary calculi formation and subsequent irritation, hyperplasia and metaplasia. Rosiglitazone was used as reference compound as this PPARgamma agonist does not cause changes in the bladder but cause lipoma/liposarcoma in rats.
2018-05-05 | GSE68604 | GEO
Project description:The carcinogenic potential of chemicals is currently evaluated with rodent life-time bioassays, which are time consuming, and expensive with respect to cost, number of animals and amount of compound required. Since the results of these 2-year bioassays are not known until quite late during development of new chemical entities, and since the short-term test battery to test for genotoxicity, a characteristic of genotoxic carcinogens, is hampered by low specificity, the identification of early biomarkers for carcinogenicity would be a big step forward. Using gene expression profiles from the livers of rats treated up to 14 days with genotoxic and non-genotoxic carcinogens we previously identified characteristic gene expression profiles for these two groups of carcinogens. We have now added expression profiles from further hepatocarcinogens and from non-carcinogens the latter serving as control profiles. We used these profiles to extract biomarkers discriminating genotoxic from non-genotoxic carcinogens and to calculate classifiers based on the support vector machine (SVM) algorithm. These classifiers then predicted a set of independent validation compound profiles with up to 88% accuracy, depending on the marker gene set. We would like to present this study as proof of the concept that a classification of carcinogens based on short-term studies may be feasible.
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Project description:Several environmental pollutants, especially organic compounds such as polycyclic aromatic hydrocarbons (PAHs) are potent carcinogenic chemicals. Exposure of different fish species to PAHs causes a high prevalence and variety of tumor lesions. To identify and compare the mode of action (MOA) of different model carcinogenic PAHs, a transcriptomic study was carried out in adult zebrafish (Danio rerio) after exposure to 0.3 mg/l of benzo(a)pyrene (B(a)P) or to 7,12-dimethylbenz(a)anthracene (DMBA), both of them dissolved in dimethyl sulfoxide (DMSO; final concentration of 0.01%). Samples for microarray analysis were taken after 1 and 2 weeks of exposure. The changes in the mRNA transcription levels over the corresponding controls were compared among treatments. Correspondence analysis was able to discriminate among treatments; factor 1 separated both sampling times while factor 2 separated the compounds. A total number of 3043 transcripts was shown to be differentially regulated in at least one of the treatments. B(a)P treatment produced regulation of sequences related to GO categories associated to cell cycle and cell division whereas DMBA regulated GO terms related to oxidation/reduction responses, responses to chemicals and response to bacterium. Both compounds were able to alter many xenobiotic metabolism related genes, especially upregulating the transcription of phase I metabolism-related genes such as cytochrome P450 members (cyp1a or cyp1b), and many cancer-related genes such as the Jun B proto-oncogene (junb). Overall, these results indicated that the exposure to both PAHs was able to differentially alter the transcription levels of genes involved in both the detoxification metabolism and the cell-cycle control, including different tumor-supressor genes and oncogens. These alterations have been often related to the appearance of tumor lesions.
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