Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Analysis of Gene Expression in 4,4'-Methylenedianiline-induced Acute Hepatotoxicity

  • Published : 2009.06.01
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Abstract

4,4'-Methylenedianiline (MDA) is an aromatic amine that is widely used in the industrial synthetic process. Genotoxic MDA forms DNA adducts in the liver and is known to induce liver damage in human and rats. To elucidate the molecular mechanisms associated with MDA-induced hepatotoxicity, we have identified genes differentially expressed by microarray approach. BALB/c male mice were treated once daily with MDA (20 mg/kg) up to 7 days via intraperitoneal injection (i.p.) and hepatic damages were revealed by histopathological observation and elevation of serum marker enzymes such as AST, ALT, ALP, cholesterol, DBIL, and TBIL. Microarray analysis showed that 952 genes were differentially expressed in the liver of MDA-treated mice and their biological functions and canonical pathways were further analyzed using Ingenuity Pathways Analysis (IPA). Toxicological functional analysis showed that genes related to hepatotoxicity such hyperplasia/hyperproliferation (Timp1), necrosis/cell death (Cd14, Mt1f, Timp1, and Pmaip1), hemorrhaging (Mt1f), cholestasis (Akr1c3, Hpx, and Slc10a2), and inflammation (Cd14 and Hpx) were differentially expressed in MDA-treated group. This gene expression profiling should be useful for elucidating the genetic events associated with aromatic amine-induced hepatotoxicity and for discovering the potential biomarkers for hepatotoxicity.

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References

  1. Alvarez, L., Jara, P., S$\acute{a}$nchez-Sabat$\acute{e}$, E., Hierro, L., Larrauri, J., D$\acute{i}$az, M.C., Camarena, C., De la Vega, A., Frauca, E., L$\acute{o}$pez-Collazo, E. and Lapunzina, P. (2004). Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. Hum. Mol. Genet., 13, 2451-2460 https://doi.org/10.1093/hmg/ddh261
  2. Bastian, P.G. (1984). Occupational hepatitis caused by methylenedianiline. Med. J., 141, 533-535
  3. Dawson, P.A., Haywood, J., Craddock, A.L., Wilson, M., Tietjen, M., Kluckman, K., Maeda, N. and Parks, J.S. (2003). Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J. Biol. Chem., 278, 33920-33927 https://doi.org/10.1074/jbc.M306370200
  4. Demeilliers, C., Jacquemin, E., Barbu, V., Mergey, M., Paye, F., Fouassier, L., Chignard, N., Housset, C. and Lomri, N.E. (2006). Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR down regulation. Hepatology, 43, 1125-1134 https://doi.org/10.1002/hep.21160
  5. Fiorucci, S., Rizzo, G., Antonelli, E., Renga, B., Mencarelli, A., Riccardi, L., Orlandi, S., Pruzanski, M., Morelli, A. and Pellicciari, R. (2005). A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J. Pharmacol. Exp. Ther., 314, 584-595 https://doi.org/10.1124/jpet.105.084905
  6. Gasson, J.C., Golde, D.W., Kaufman, S.E., Westbrook, C.A., Hewick, R.M., Kaufman, R.J., Wong, G.G., Temple, P.A., Leary, A.C. and Brown, E.L. (1985). Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature, 315, 768-771 https://doi.org/10.1038/315768a0
  7. Hamadeh, H.K., Bushel, P.R., Jayadev, S., Martin, K., DiSorbo, O., Sieber, S., Bennett, L., Tennant, R., Stoll, R., Barrett, J.C., Blanchard, K., Paules, R.S. and Afshari, C.A. (2002). Gene expression analysis reveals chemicalspecific profiles. Toxicol. Sci., 67, 219-231 https://doi.org/10.1093/toxsci/67.2.219
  8. Heijne, W.H., Slitt, A.L., van Bladeren, P.J., Groten, J.P., Klaassen, C.D., Stierum, R.H. and van Ommen, B. (2004). Bromobenzene-induced hepatotoxicity at the transcriptome level. Toxicol. Sci., 79, 411-422 https://doi.org/10.1093/toxsci/kfh128
  9. Huang, Q., Jin, X., Gaillard, E.T., Knight, B.L., Pack, F.D., Stoltz, J.H., Jayadev, S. and Blanchard, K.T. (2004). Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants. Mutat. Res., 549, 147-167 https://doi.org/10.1016/j.mrfmmm.2003.12.020
  10. Liu, X.W., Taube, M.E., Jung, K.K., Dong, Z., Lee, Y.J., Roshy, S., Sloane, B.F., Fridman, R. and Kim, H.R. (2005). Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells from extrinsic cell death: a potential oncogenic activity of tissue inhibitor of metalloproteinase-1. Cancer Res., 65, 898-906
  11. Martelli, A., Carrozzino, R., Mattioli, F. and Brambilla, G. (2002). DNA damage induced by 4,4'-methylenedianiline in primary cultures of hepatocytes and thyreocytes from rats and humans. Toxicol. Appl. Pharmacol., 182, 219-225 https://doi.org/10.1006/taap.2002.9446
  12. Martin, D.C., Fowlkes, J.L., Babic, B. and Khokha, R. (1999). Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1. J. Cell. Biol., 146, 881-892 https://doi.org/10.1083/jcb.146.4.881
  13. Masters, B.A., Kelly, E.J., Quaife, C.J., Brinster, R.L. and Palmiter, R.D. (1994). Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium. Proc. Natl. Acad. Sci. U.S.A., 91, 584-588 https://doi.org/10.1073/pnas.91.2.584
  14. McQueen, C.A. and Williams, G.M. (1990). Review of the genotoxicity and carcinogenicity of 4,4'-methylene-dianiline and 4,4'-methylene-bis-2-chloroaniline. Mutat. Res., 239, 133-142 https://doi.org/10.1016/0165-1110(90)90034-9
  15. Murphy, F.R., Issa, R., Zhou, X., Ratnarajah, S., Nagase, H., Arthur, M.J., Benyon, C. and Iredale, J.P. (2002). Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J. Biol. Chem., 277, 11069-11076 https://doi.org/10.1074/jbc.M111490200
  16. Nichols, L. (2004). The Epping Jaundice outbreak: mortality after 38 years of follow-up. Int. Arch. Occup. Environ. Health, 77, 592-594 https://doi.org/10.1007/s00420-004-0565-7
  17. Oh, J.H., Park, H.J., Hwang, J.Y., Jeong, S.Y., Lim, J.S., Kim. Y.B. and Yoon, S. (2007). Gene expression analysis of hepatic response induced by gentamicin in mice. Mol. Cell. Toxicol., 3, 60-67
  18. Oh, J.H., Yang, M.J., Yang, Y.S., Park, H.J., Heo, S.H., Lee, E.H., Song, C.W. and Yoon, S. (2009a). Microarray-based analysis of the lung recovery process after stainless steel welding fume exposure in Sprague–Dawley rats. Inhal. Tox., 21, 1-27
  19. Oh, J.H., Oh, M.J., Park, H.J., Kim, S.J., Park, S.M., Yoon, H.J., Cho, J.W. and Yoon, S. (2009b). Analysis of gene expression in the testes of mice exposed to bisphenol A and nonylphenol. Biochip J., in press
  20. Oh, J.H., Park, H.J., Jeong, S.Y., Lim, J.S., Hwang, J.Y., Kim. Y.B. and Yoon, S. (2006). Gene expression profiling of early renal toxicity induced by gentamicin in mice. Mol. Cell. Toxicol., 2, 185-192
  21. Robert, A., Ducos, P. and Francin, J.M. (1995). Determination of urinary 4,4'-methylenedianiline and its acetylated metabolites by solid-phase extraction and HPLC analysis with UV and electrochemical detection. Int. Arch. Occup. Environ. Health, 68, 44-51 https://doi.org/10.1007/BF01831632
  22. Santa Cruz, V., Liu, H., Kaphalia, L. and Kanz, M.F. (2007). Effects of methylenedianiline on tight junction permeability of biliary epithelial cells in vivo and in vitro. Toxicol. Lett., 169, 13-25 https://doi.org/10.1016/j.toxlet.2006.11.007
  23. Schutze, D., Sepai, O., Lewalter, J., Miksche, L., Henschler, D. and Sabbioni, G. (1995). Biomonitoring of workers exposed to 4,4'-methylenedianiline or 4,4'-methylenediphenyl diisocyanate. Carcinogenesis, 16, 573-582 https://doi.org/10.1093/carcin/16.3.573
  24. Shibue, T., Takeda, K., Oda, E., Tanaka, H., Murasawa, H., Takaoka, A., Morishita, Y., Akira, S., Taniguchi, T. and Tanaka, N. (2003). Integral role of Noxa in p53-mediated apoptotic response. Genes Dev., 17, 2233-2238 https://doi.org/10.1101/gad.1103603
  25. Strohecker, A.M., Yehiely, F., Chen, F. and Cryns, V.L. (2008). Caspase cleavage of HER-2 releases a bad-like cell death effector. J. Biol. Chem., 283, 18269-18282 https://doi.org/10.1074/jbc.M802156200
  26. Yin, M., Bradford, B.U., Wheeler, M.D., Uesugi, T., Froh, M., Goyert, S.M. and Thurman, R.G. (2001). Reduced early alcohol-induced liver injury in CD14-deficient mice. J. Immunol., 166, 4737-4742 https://doi.org/10.4049/jimmunol.166.7.4737
  27. Zhang, X., Lambert, J.C., Doll, M.A., Walraven, J.M., Arteel, G.E. and Hein, D.W. (2006). 4,4'-methylenedianilineinduced hepatotoxicity is modified by N-acetyltransferase 2 (NAT2) acetylator polymorphism in the rat. J. Pharmacol. Exp. Ther., 316, 289-294 https://doi.org/10.1124/jpet.105.093302
  28. Zhang, G., Park, M.A., Mitchell, C., Walker, T., Hamed, H., Studer, E., Graf, M., Rahmani, M., Gupta, S., Hylemon, P.B., Fisher, P.B., Grant, S. and Dent, P. (2008). Multiple cyclin kinase inhibitors promote bile acid-induced apoptosis and autophagy in primary hepatocytes via p53-CD95-dependent signaling. J. Biol. Chem., 283, 24343-24358 https://doi.org/10.1074/jbc.M803444200

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