Hepatic Gene Expression Analysis of 1, 1-Dichloroethylene Treated Mice

  • Yoon, Seok-Joo (Toxicogenomics Team, Korea Institute of Toxicology) ;
  • Oh, Jung-Hwa (Toxicogenomics Team, Korea Institute of Toxicology) ;
  • Park, Han-Jin (Toxicogenomics Team, Korea Institute of Toxicology) ;
  • Kim, Yong-Bum (Clinical Pathology Team, Korea Institute of Toxicology)
  • Published : 2007.06.30

Abstract

1, 1-dichloroethylene (DCE) is well known hepatotoxicant as a model acute hepatotoxicity and selectively injure the bile canalicular membrane of centrilobular hepatocytes. In this study, we investigated hepatic gene expression and histopathological changes in response to DCE treatment. DCE was administered once daily at 20 mg/kg up to 14 days via intraperitoneal injection. Five mice were used in each test group and were sacrificed at 1, 7, and 14 days. Serum biochemical and histopathological analysis were performed for evaluation of hepatotoxicity level. Direct bilirubin and total bilirubin activities were slightly elevated in treated group at 7 days. DCE treatment for 7 days resulted in centrilobular hepatocyte hypertrophy and hepatocyte vacuolation, and mild hepatocyte vacuolation and high hepatocyte basophilia were observed in 14 days treated group. One hundred twenty three up-regulated genes and 445 down-regulated genes with over 2-fold changes between treated and control group at each time point were used for pathway analysis. These data may contribute in understanding the molecular mechanism DCE-induced hepatotoxicity.

Keywords

References

  1. OEHHA, Chronic toxicity summary, Determination of noncancer chronic reference exposure levels Batch 2A:A97-103 (2000)
  2. Kanz, M. F. & Reynolds, E. S. Early effects of 1, 1- dichloroethylene on canalicular and plasma membranes: Ultrastructure and stereology. Exp. Mol. Pathol. 44:93-110 (1986) https://doi.org/10.1016/0014-4800(86)90037-7
  3. Moslen, M. T., Kanz, M. F., Bhatia, J. & Catarau, E. M. Two cannula method for parenteral infusion and serial blood sampling in the freely moving rat. J. Enterol. Parenter. Nutr. 12:633-638 (1988) https://doi.org/10.1177/0148607188012006633
  4. Chieco, P., Moslen, M. T. & Reynolds, E. S. Histochemical evidence that plasma and mitochondrial membranes are primary foci of hepatocellular injury caused by 1, 1-dichloroethylene. Lab. Invest. 46:413- 421 (1982)
  5. Forkert, P. G., Stringer, V. & Troughton, K. M. Pulmonary toxicity of 1, 1-dichloroethylene: correlation of early changes with covalent binding. Can. J. Physiol. Pharmacol. 64:112-121 (1986) https://doi.org/10.1139/y86-017
  6. Reynolds, E. S. et al. Hepatotoxicity of vinyl chloride and 1, 1-dichloroethylene. Role of mixed function oxidase system. Am. J. Pathol. 81:219-236 (1975)
  7. Jones, B. K. & Hathway, D. E. The biological fate of vinylidene chloride in rats. Chem. Biol. Interact. 20: 27-41 (1978) https://doi.org/10.1016/0009-2797(78)90078-9
  8. Jones, B. K. & Hathway, D. E. Differences in metabolism of vinylidene chloride between mice and rats. Br. J. Cancer 37:411-417 (1978) https://doi.org/10.1038/bjc.1978.61
  9. Liebler, D. C., Meredith, M. J. & Guengerich, F. P. Formation of glutathione conjugates by reactive metabolites of vinylidene chloride in microsomes and isolated hepatocytes. Cancer Res. 45:186-193 (1985)
  10. Forkert, P. G. & Moussa, M. 1, 1-Dichloroethylene elicits dose-dependent alterations in covalent binding and glutathione in murine liver. Drug Metab. Dispos. 19:580-586 (1991)
  11. Molsen, M. T. & Kanz, M. F. Biliary excretion of marker solutes by rats with 1, 1-dichloroethylene-induced bile canalicular injury. Toxicol. Appl. Pharmacol. 122:117-130 (1993) https://doi.org/10.1006/taap.1993.1179
  12. Marumo, T., Fukusato, T. & Takikawa, H. Biliary excretion of bile acids and organic anions in rats with dichloroethylene-induced bile canalicular injury. J. Gastroenterol. 39:981-987 (2004) https://doi.org/10.1007/s00535-004-1431-9
  13. Hwang, J. Y. et al. Toxicogenomics Study on $\alpha$- Naphthylisothiocyanate (ANIT) Induced Hepatotoxictiy in Mice. Mol. Cell. Toxicol. 2:48-53 (2006)
  14. Lim, J. S. et al. Effects of phalloidine on hepatic gene expression in mice. Intl. J. Toxicol. (2007) (in press)
  15. Myung, S. J. et al. Bile acid-mediated thrombospondin- 1 induction in hepatocytes leads to transforming growth factor-b-dependent hepatic stellate cell activation. Biochem. Biophys. Res. Commun. 353:1091- 1096 (2007) https://doi.org/10.1016/j.bbrc.2006.12.157
  16. Barcellos, M. H. & Dix, D. A. Redox-mediated activation of latent transforming growth factor-beta 1. Mol. Endocrin. 10:1077-1083 (1996) https://doi.org/10.1210/me.10.9.1077
  17. Flisiak, R. & Prokopowicz, D. Transforming Growth Factor-b1 as a Surrogate Marker of Hepatic Dysfunction in Chronic Liver Diseases. Clin. Chem. Lab. Med. 38:1129-1131 (2000) https://doi.org/10.1515/CCLM.2000.170
  18. Ito, S. et al. $\beta$Klotho: A New Kid on the Bile Acid Biosynthesis Block. J. Clin. Invest. 115:2202-2208 (2005) https://doi.org/10.1172/JCI23076