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Publications (2)3.9 Total impact

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    ABSTRACT: 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.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 05/2012; 747(2):164-75. · 3.90 Impact Factor
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    ABSTRACT: It is known that genotoxic N-nitroso carcinogens induce DNA damage in mouse liver within a few hours and induce mutations within 28 days after their administration. However, related-gene expression changes at these time points in liver were not fully elucidated. Differential gene expression induced by two genotoxic N-nitroso carcinogens in mouse liver was examined 4 h and 28 days after their administration with in-house oligonucleotide microarray (268 genes) and quantitative real-time PCR, and compared to that of a non-genotoxic carcinogen and a non-carcinogenic toxin. Diethylnitrosamine (DEN, 80 mg/kg bw), dipropylnitrosamine (DPN, 250 mg/kg bw), phenobarbital sodium (30 mg/kg bw) and ethanol (1000 mg/kg bw) were injected intraperitoneally into groups of male 9-week-old B6C3F1 mice and liver was dissected after 4 h and 28 days. mRNA from pooled livers was reverse-transcribed to cDNA, and Cy3- and Cy5-labeled cDNA was competitively hybridized with in-house made microarray, scanned and analyzed; additionally, quantitative real-time PCR was performed for selected genes. Differential gene expression between two genotoxic N-nitroso carcinogens and phenobarbital and ethanol was observed in 11 genes 4 h after administration, including seven tumor suppressor p53 target genes, viz. c-Jun, Ccng1, Mdm2, p21, Bax, Hsp27 and Snk; the other genes were Mbd1, Hmox-1, Ccnf and Rad52. However, only some degree of differential gene expression of p21, Ccng1 and Snk was observed 28 days after administration; no other differentially-expressed genes were evident. The present results suggest that DEN and DPN induce differential gene expression in p53 target genes in liver within a few hours after administration and that these acute responses remained only partially in liver after 28 days.
    Genes and Environment 09/2007; 29(3):115-127.