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http://dx.doi.org/10.5487/TR.2007.23.1.055

Gene Expression Profiling in Diethylnitrosamine Treated Mouse Liver: From Pathological Data to Microarray Analysis  

Kim, Ji-Young (Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Yoon, Seok-Joo (Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Park, Han-Jin (Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Kim, Yong-Bum (Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Cho, Jae-Woo (Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Koh, Woo-Suk (Korea Institute of Toxicology, Korea Research Institute of Chemical Technology)
Lee, Michael (Department of Biology, College of Natural Sciences, University of Incheon)
Publication Information
Toxicological Research / v.23, no.1, 2007 , pp. 55-63 More about this Journal
Abstract
Diethylnitrosamine (DEN) is a nitrosamine compound that can induce a variety of liver lesions including hepatic carcinoma, forming DNA-carcinogen adducts. In the present study, microarray analyses were performed with Affymetrix Murine Genome 430A Array in order to identify the gene-expression profiles for DEN and to provide valuable information for the evaluation of potential hepatotoxicity. C57BL/6NCrj mice were orally administered once with DEN at doses of 0, 3, 7 and 20 mg/kg. Liver from each animal was removed 2, 4, 8 and 24 hrs after the administration. The histopathological analysis and serum biochemical analysis showed no significant difference in DEN-treated groups compared to control group. Conversely, the principal component analysis (PCA) profiles demonstrated that a specific normal gene expression profile in control groups differed clearly from the expression profiles of DEN-treated groups. Within groups, a little variance was found between individuals. Student's t-test on the results obtained from triplicate hybridizations was performed to identify those genes with statistically significant changes in the expression. Statistical analysis revealed that 11 genes were significantly downregulated and 28 genes were upregulated in all three animals after 2 h treatment at 20 mg/kg. The upregulated group included genes encoding Gdf15, JunD1, and Mdm2, while the genes including Sox6, Shmt2, and SIc6a6 were largely down regulated. Hierarchical clustering of gene expression also allowed the identification of functionally related clusters that encode proteins related to metabolism, and MAPK signaling pathway. Taken together, this study suggests that match with a toxicant signature can assign a putative mechanism of action to the test compound if is established a database containing response patterns to various toxic compounds.
Keywords
Microarray; Diethylnitrosamine; Histopathology; Gene expression; Toxicogenomics;
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1 Ben-Zur, T., Feige, E., Motro, B. and Wides, R. (2000). The mammalian Odz gene family: Homologs of a Drosophila pair-rule gene with expression implying distinct yet overlapping developmental roles. Dev. Biol., 217, 107-120   DOI   ScienceOn
2 Garrow, T.A., Brenner, A.A., Whitehead, V.M., Chen, X.-N., Duncan, R.G., Korenberg, J.R. and Shane, B. (1993). Cloning of human cDNAs encoding mitochondrial and cytosolic serine hydroxymethyltransferases and chromosomal localization. J. Biol. Chem., 268, 11910-11916
3 Kaasik, K. and Lee, C.C. (2004). Reciprocal regulation of haem biosynthesis and the circadian clock in mammals. Nature, 430, 467-471   DOI   ScienceOn
4 Oyake, T., Itoh, K., Motohashi, H., Hayashi, N., Hoshino, H., Nishizawa, M., Yamamoto, M. and Igarashi, K. (1996). Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol. Cell. Biol., 16, 6083-6095   DOI
5 Petit, M.M.R., Mols, R., Schoenmakers, E.F.P.M., Mandahl, N. and Van de Ven, W.J.M. (1996). LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family. Genomics, 36, 118-129   DOI   ScienceOn
6 Qian, C., Idoate, M., Bilbao, R., Sangro, B., Bruna, O., Vazquez, J. and Prieto, J. (1997). Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamineinduced hepatocellular carcinoma. Human Gene Ther., 8, 349-358   DOI   ScienceOn
7 Williams, G.M., Iatropoulos, M.J., Wang, C.X., Ali, N., Rivenson, A., Peterson, L.A., Schulz, C. and Gebhardt, R. (1996). Diethylnitrosamine exposure-responses for DNA damage, centrilobular cytotoxicity, cell proliferation and carcinogenesis in rat liver exhibit some non-linearities. Carcinogenesis, 17, 2253-2258   DOI   ScienceOn
8 Schoenherr, C.J. and Anderson, D.J. (1995). The neuronrestrictive silencer factor (NRSF): A coordinate repressor of multiple neuron-specific genes. Science, 267, 1360- 1363   DOI   ScienceOn
9 Smart, D.E., Green, K., Oakley, F., Weitzman, J.B., Yaniv, M.,Reynolds, G., Mann, J., Millward-Sadler, H. and Mann, D.A. (2006). JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation. Hepatology, 44, 1432-1440   DOI   ScienceOn
10 Pennie, W.D. and Kimber, I. (2002). Toxicogenomics: transcript profiling and potential application to chemical allergy. Toxicol. In Vitro, 16, 319-326   DOI   ScienceOn
11 Tatematsu, M., Nagamine, Y. and Farber, E. (1988). Stable phenotypic expression of glutathione S-transferase placental type and unstable phenotypic expression of $\gamma$- glutamyl transpeptidase in rat liver preneoplastic and neoplastic lesions. Carcinogenesis, 9, 215-220   DOI   ScienceOn
12 Momand, J., Zambetti, G.P., Olson, D.C., George, D.L. and Levine, A.J. (1992). The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell, 69, 1237-1245   DOI   ScienceOn
13 Yokoyama-Kobayashi, M., Saeki, M., Sekine, S. and Kato, S. (1997). Human cDNA encoding a novel TGF-$\beta$ superfamily protein highly expressed in placenta. J. Biochem., 122, 622-626   DOI   ScienceOn
14 Connor, F., Wright, E., Denny, P., Koopman, P. and Ashworth, A. (1995). The Sry-related HMG box-containing gene Sox6 is expressed in the adult testis and developing nervous system of the mouse. Nucleic Acids Res., 23, 3365-3372   DOI
15 Bishop, D.F., Henderson, A.S. and Astrin, K.H. (1990). Human $\delta$-aminolevulinate synthase: Assignment of the housekeeping gene to 3p21 and the erythroid-specific gene to the X chromosome. Genomics, 7, 207-214   DOI
16 Driver, H.E. and McLean, A.E. (1986). Dose-response relationships for initiation of rat liver tumours by diethylnitrosamine and promotion by phenobarbitone or alcohol. Food Chem. Toxicol., 24, 241-245   DOI   ScienceOn
17 Waring, J.F., Jolly, R.A., Ciurlionis, R., Lum, P.Y., Praestgaard, J.T., Morfitt, D.C., Buratto, B., Roberts, C., Schadt, E. and Ulrich, R.G. (2001). Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles. Toxicol. Appl. Pharmacol., 175, 28-42   DOI   ScienceOn
18 Nakae, D., Kobayashi, Y., Akai, H., Andoh, N., Satoh, H., Ohashi, K., Tsutsumi, M. and Konishi, Y. (1997). Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiethylamine. Cancer Res., 57, 1281-1287
19 Wang, J.-W., Howson, J., Haller, E. and Kerr, W.G. (2001a). Identification of a novel lipopolysaccharide-inducible gene with key features of both a kinase anchor proteins and chs1/beige proteins. J. Immunol., 166, 4586-4595   DOI
20 Wang, Y., Devereux, W., Stewart, T.M. and Casero, R.A. Jr. (2001b). Characterization of the interaction between the transcription factors human polyamine modulated factor (PMF-1) and NF-E2-related factor 2 (Nrf-2) in the transcriptional regulation of the spermidine/spermine N(1)- acetyltransferase (SSAT) gene. Biochem. J., 355, 45-49   DOI
21 Fielden, M.R. and Zacharewski, T.R. (2001). Challenges and limitations of gene expression profiling in mechanistic and predictive toxicology. Toxicol. Sci., 60, 6-10   DOI   ScienceOn
22 Lamour, V., Quevillon, S., Diriong, S., N'Guyen, V.C., Lipinski, M. and Mirande, M. (1994). Evolution of the Glx-tRNA synthetase family: The glutaminyl enzyme as a case of horizontal gene transfer. Proc. Nat. Acad. Sci. U.S.A., 91, 8670-8674
23 Uchida, S., Kwon, H.M., Yamauchi, A., Preston, A.S., Marumo, F. and Handler, J.S. (1992). Molecular cloning of the cDNA for an MDCK cell Na(+)- and Cl(-)-dependent taurine transporter that is regulated by hypertonicity. Proc. Nat. Acad. Sci. U.S.A., 89, 8230-8234
24 Bach, I. (2000). The LIM domain: Regulation by association. Mech. Dev., 91, 5-17   DOI   ScienceOn
25 Shivapurkar, N., Hoover, K.L. and Poirier, L.A. (1986). Effect of methionine and choline on liver tumor promotion by phenobarbital and DDT in diethylnitrosamine-initiated rats. Carcinogenesis, 547-550
26 Qin, L.X. and Tang, Z.Y. (2002). The prognostic molecular markers in hepatocellular carcinoma. World J. Gastroenterol., 8, 385-392   DOI
27 Bannasch, P., Hacker, H.J., Klimek, F. and Mayer, D. (1984). Hepatocellular glycogenosis and related pattern of enzymatic changes during hepatocarcinogenesis. Adv. Enzyme Regul., 22, 97-121   DOI   ScienceOn
28 LeBoeuf, R.A., Laishes, B.A. and Hoekstra, W.G. (1985).Effects of dietary selenium concentration on the development of enzyme-altered liver foci and hepatocellular carcinoma induced by diethylnitrosamine or N-acetylaminofluorene in rats. Cancer Res., 45, 5489-5495
29 Brown, P.O. and Botstein, D. (1999). Exploring the new world of the genome with DNA microarrays. Nat. Genet., 21, 33-37   DOI   ScienceOn
30 Eisen, M.B., Spellman, P.T., Brown, P.O. and Bostein, D. (1998). Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. U.S.A., 95, 14863-14868
31 Yeung, K.Y. and Ruzzo, W.L. (2001). Principal component analysis for clustering gene expression data. Bioinformatics, 17, 763-774   DOI   ScienceOn