Discrimination of genotoxic and non-genotoxic hepatocarcinogens by statistical analysis based on gene expression profiling in the mouse liver as determined by quantitative real-time PCR
| Autor: | Emiko Okada, Akihisa Maeda, Shuichi Hamada, Yohei Miyamoto, Yasuyoshi Ishikawa, Ayami Tadakuma, Masakatsu Natsume, Shizuyo Sutou, Hiroshi Honda, Kazunori Narumi, Tomohiro Sakuma, Akiko Koeda, Izumi Hanahara, Takashi Watanabe, Madoka Nakajima, Yohei Fujiishi, Michiasa Hirayama, Hisakazu Sanada, Keiyu Oshida, Takayoshi Suzuki, Mahoko Kido, Wakako Ohyama, Rina Minamiguchi, Chie Furihata |
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| Rok vydání: | 2012 |
| Předmět: |
Male
DNA repair DNA damage Gene Expression Profiling Health Toxicology and Mutagenesis Double Effect Principle Cell cycle Biology Real-Time Polymerase Chain Reaction Molecular biology Gene expression profiling Mice Liver Neoplasms Experimental Real-time polymerase chain reaction Liver Gene expression Carcinogens Genetics Animals DNA microarray Gene Injections Intraperitoneal Mutagens |
| Zdroj: | Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 747:164-175 |
| ISSN: | 1383-5718 |
| DOI: | 10.1016/j.mrgentox.2012.04.011 |
| Popis: | The general aim of the present study is to discriminate between mouse genotoxic and non-genotoxic hepatocarcinogens via selected gene expression patterns in the liver as analyzed by quantitative real-time PCR (qPCR) and statistical analysis. qPCR was conducted on liver samples from groups of 5 male, 9-week-old B6C3F(1) mice, at 4 and 48h following a single intraperitoneal administration of chemicals. We quantified 35 genes selected from our previous DNA microarray studies using 12 different chemicals: 8 genotoxic hepatocarcinogens (2-acetylaminofluorene, 2,4-diaminotoluene, diisopropanolnitrosamine, 4-dimethylaminoazobenzene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N-nitrosomorpholine, quinoline and urethane) and 4 non-genotoxic hepatocarcinogens (1,4-dichlorobenzene, dichlorodiphenyltrichloroethane, di(2-ethylhexyl)phthalate and furan). A considerable number of genes exhibited significant changes in their gene expression ratios (experimental group/control group) analyzed statistically by the Dunnett's test and Welch's t-test. Finally, we distinguished between the genotoxic and non-genotoxic hepatocarcinogens by statistical analysis using principal component analysis (PCA) of the gene expression profiles for 7 genes (Btg2, Ccnf, Ccng1, Lpr1, Mbd1, Phlda3 and Tubb2c) at 4h and for 12 genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a, Gdf15, Lrp1, Mbd1, Phlda3, Plk2 and Tubb2c) at 48h. Seven major biological processes were extracted from the gene ontology analysis: apoptosis, the cell cycle, cell proliferation, DNA damage, DNA repair, oncogenes and tumor suppression. The major, biologically relevant gene pathway suggested was the DNA damage response pathway, resulting from signal transduction by a p53-class mediator leading to the induction of apoptosis. Eight genes (Aen, Bax, Btg2, Ccng1, Cdkn1a, Gdf15, Phlda3 and Plk2) that are directly associated with Trp53 contributed to the PCA. The current findings demonstrate a successful discrimination between genotoxic and non-genotoxic hepatocarcinogens, using qPCR and PCA, on 12 genes associated with a Trp53-mediated signaling pathway for DNA damage response at 4 and 48 h after a single administration of chemicals. |
| Databáze: | OpenAIRE |
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