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Changes in the Expression of Ras-family Genes in Rats Exposed to Formaldehyde by Inhalation

  • Li, Guang-Yong (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Lee, Hye-Young (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Choi, You-Jin (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Lee, Mi-Ock (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University) ;
  • Shin, Ho-Sang (Department of Environmental Education and Abuse Drug Research Center, Kongju National University) ;
  • Kim, Hyeon-Young (Chemical Safety and Health Research Center, Occupational Safety & Health Research Institute) ;
  • Lee, Sung-Bae (Chemical Safety and Health Research Center, Occupational Safety & Health Research Institute) ;
  • Lee, Byung-Hoon (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University)
  • Published : 2008.09.01

Abstract

Exposure to formaldehyde(FA) is closely associated with adverse health effects such as irritation, inflammation, and squamous cell carcinomas of the nasal cavities. Owing to its rapid metabolism and elimination, exposure to FA does not always result in an increased concentration in blood or urine of animals and humans. Therefore, the development of biomarkers for FA exposure is necessary for risk assessment. In the present study, the effects of FA were investigated on the expression of genes involved in the MAPK pathway in vitro and results confirmed in rats exposed to FA by inhalation. Treatment of Hs 680.Tr human tracheal epithelial cells with FA induced gene expression for PDGFA, TNFSF11, SHC1, and HRAS. HRAS expression was also increased in tracheas of rats exposed to FA. In addition, FA exposure induced the expression of RASSF4, a member of the Rasassociation domain family of Ras effectors, in rat tracheas. In conclusion, data showed FA-inducible expression of genes involved in the MAPK pathway occurred and increased expression of HRAS and RASSF4 was noted in rat tracheas subchronically exposed to FA by inhalation. These genes may serve as molecular targets of FA toxicity facilitating the understanding of the toxic mechanism.

Keywords

References

  1. Al-Nabulsi, I. and Wheeler, K.T. (1999). Radiation-induced DNA damage in tumors and normal tissues: V. Influence of pH and nutrient depletion on the formation of DNA-protein crosslinks in irradiated partially and fully hypoxic tumor cells. Radiat. Res., 151, 188-194 https://doi.org/10.2307/3579769
  2. Alexandersson, R., Hendenstierna, G. and Kolmodin-Hedman, B. (1988). Respiratory hazards associated with exposure to formaldehyde and solvents in acid-curing paints. Arch. Environ. Health, 43, 222-227 https://doi.org/10.1080/00039896.1988.9934937
  3. Caldas, E.F., Trudequ, W.L. and Ledford, D.K. (1994). Environmental control of indoor biologic agents. J. Allergy Clin. Immunol., 94, 404-412 https://doi.org/10.1053/ai.1994.v94.a57115
  4. Calipel, A., Lefevre, G., Pouponnot, C., Mouriaux, F., Eychene, A. and Mascarelli, F. (2003). Mutation of B-Raf in human choroidal melanoma cells mediates cell proliferation and transformation through the MEK/ERK pathway. J. Biol. Chem., 278, 42409-42418 https://doi.org/10.1074/jbc.M308709200
  5. Casanova, M., Deyo, D.F. and Heck, H.D. (1989). Covalent binding of inhaled formaldehyde to DNA in the nasal mucosa of Fischer 344 rats: Analysis of formaldehyde and DNA by high-performance liquid chromatography and provisional pharmacokinetic interpretation. Fundam. Appl. Toxicol., 12, 397-417 https://doi.org/10.1016/0272-0590(89)90015-8
  6. Chakrabarti, S.K., Bai, C. and Subramanian, K.S. (2001). DNA-protein crosslinks induced by nickel compounds in isolated rat lymphocytes: Role of reactive oxygen species and specific amino acids. Toxicol. Appl. Pharmacol., 170, 153-165 https://doi.org/10.1006/taap.2000.9097
  7. Chang, C.C., Ruhl, R.A., Halpern, G.M. and Gershwin, M.E. (1993). The sick building syndrome. I. Definition and epidemiological considerations. J. Asthma, 30, 285-295 https://doi.org/10.3109/02770909309054529
  8. Danhof, M., Alvan, G., Dahl, S.G., Kuhlmann, J. and Paintaud, G. (2005). Mechanism-based pharmacokinetic-pharmacodynamic modeling-a new classification of biomarkers. Pharm. Res., 22, 1432-1437 https://doi.org/10.1007/s11095-005-5882-3
  9. Feick, P., Haas, S.R., Singer, M.V. and Boecker, U. (2006). Low-dose exposure of intestinal epithelial cells to formaldehyde results in MAP kinase activation and molecular alteration of the focal adhesion protein paxillin. Toxicology, 219, 60-72 https://doi.org/10.1016/j.tox.2005.11.004
  10. Gottschling, L.M., Beaulieu, H.J. and Melvin, W.W. (1984). Monitoring of formic acid in urine of humans exposed to low levels of formaldehyde. Am. Ind. Hyg. Assoc. J., 45, 19-23 https://doi.org/10.1080/15298668491399299
  11. Harada, K., Hara, K., Wei, C.N., Ohmori, S., Matsushita, O. and Ueda, A. (2007). Case study of volatile organic compounds in indoor air of a house before and after repair where sick building syndrome occurred. Int. J. Immunopathol. Pharmacol., 20, 69-74
  12. Heck, H.D., Casanova, M., Dodd, P.B., Schachter, E.N., Witek, T.J. and Tosun, T. (1985). Formaldehyde ($CH_2O$) concentrations in the blood of humans and Fischer-344 rats exposed to $CH_2O$ under controlled conditions. Am. Ind. Hyg. Assoc. J., 46, 1-3 https://doi.org/10.1080/15298668591394275
  13. Heck, H.D., Casanova, M. and Starr, T.B. (1990). Formaldehyde toxicity--New understanding. Crit. Rev. Toxicol., 20, 397-426 https://doi.org/10.3109/10408449009029329
  14. International Agency for Research on Cancer. (2004). IARC classifies formaldehyde as carcinogenic to humans. From: http://www.iarc.fr/ENG/Press_Releases/archives/pr153a.html. (Retrieved Feb. 14, 2008)
  15. Im, H., Oh, E., Mun, J., Khim, J.Y., Lee, E., Kang, H.S., Kim, E., Kim, H., Won, N.H., Kim, Y.H., Jung, W.W. and Sul, D. (2006). Evaluation of toxicological monitoring markers using proteomic analysis in rats exposed to formaldehyde. J. Proteome Res., 5, 1354-1366 https://doi.org/10.1021/pr050437b
  16. Kamata, E., Nakadate, M., Uchida, O., Ogawa, Y., Suzuki, S., Kaneko, T., Saito, M. and Kurokawa, Y. (1997). Results of a 28-month chronic inhalation toxicity study of formaldehyde in male Fisher-344 rats. J. Toxicol. Sci., 22, 239-254
  17. Kane, L.E. and Alarie, Y. (1977). Sensory irritation to formaldehyde and acrolein during single and repeated exposures in mice. Am. Ind. Hyg. Assoc. J., 38, 509-522 https://doi.org/10.1080/0002889778507665
  18. Kerns, W.D., Pavkov, K.L., Donofrio, D.J., Gralla, E.J. and Swenberg, J.A. (1983). Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res., 43, 4382-4392
  19. Kim, W.J., Terada, N., Nomura, T., Takahashi, R., Lee, S.D., Park, J.H. and Konno, A. (2002). Effect of formaldehyde on the expression of adhesion molecules in nasal microvascular endothelial cells: the role of formaldehyde in the pathogenesis of sick building syndrome. Clin. Exp. Allergy, 32, 287-295 https://doi.org/10.1046/j.1365-2222.2002.01301.x
  20. Lee, M.H., Kim, Y.A., Na, T.Y., Kim, S.H., Shin, Y.K., Lee, B.H., Shin, H.S. and Lee, M.O. (2008a). Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology, 243, 224-235 https://doi.org/10.1016/j.tox.2007.10.007
  21. Lee, M.H., Lee, B.H., Shin, H.S. and Lee, M.O. (2008b). Elevated Levels of PDGF Receptor and MDM2 as Potential Biomarkers for Formaldehyde Intoxication. Toxicol. Res., 24, 45-49 https://doi.org/10.5487/TR.2008.24.1.045
  22. Leevers, S.J., Paterson, H.F. and Marshall, C.J. (1994). Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature, 369, 411-414 https://doi.org/10.1038/369411a0
  23. Li, G.Y., Lee, H.Y., Shin, H.S., Kim, H.Y., Lim, C.H. and Lee, B.H. (2007). Identification of gene markers for formaldehyde exposure in human. Environ. Health Persp., 115, 1460-1466
  24. Mansour, S.J., Matten, W.T., Hermann, A.S., Candia, J.M., Rong, S., Fukasawa, K., Vande Woude, G.F. and Ahn, N.G. (1994). Transformation of mammalian cells by constitutively active MAP kinase kinase. Science, 265, 966-970 https://doi.org/10.1126/science.8052857
  25. Maronpot, R.R., Miller, R.A., Clarke, W.J., Westerberg, R.B., Decker, J.R. and Moss, O.R. (1986). Toxicity of formaldehyde vapor in B6C3F1 mice exposed for 13 weeks. Toxicology, 41, 253-266 https://doi.org/10.1016/0300-483X(86)90180-0
  26. Monticello, T.M., Swenberg, J.A., Gross, E.A., Leininger, J.R., Kimbell, J.S., Seilkop, S., Starr, T.B., Gibson, J.E. and Morgan, K.T. (1996). Correlation of regional and nonlinear formaldehyde-induced nasal cancer with proliferating populations of cells. Cancer Res., 56, 1012-1022
  27. Naya, M. and Nakanishi, J. (2005). Risk assessment of formaldehyde for the general population in Japan. Reg. Toxicol. Pharmacol., 43, 232-248 https://doi.org/10.1016/j.yrtph.2005.08.002
  28. Shaham, J., Bomstein, Y., Gurvich, R., Rashkovsky, M. and Kaufman, Z. (2003). DNA-protein crosslinks and p53 protein expression in relation to occupational exposure to formaldehyde. Occup. Environ. Med., 60, 403-409 https://doi.org/10.1136/oem.60.6.403
  29. Shiba, M., Marchok, A.C. and Klein-Szanto, A.J. (1984). The effects of formaldehyde gas in a flow-through rat tracheal implant system. Toxicology, 30, 317-325 https://doi.org/10.1016/0300-483X(84)90142-2
  30. Sun, H., Tonks, N. and Bar-Sagi, D. (1994). Inhibition of Rasinduced DNA synthesis by expression of the phosphatase MKP-1. Science, 266, 285-288 https://doi.org/10.1126/science.7939666
  31. Takai, Y., Sasaki, T. and Matozaki, T. (2001). Small GTP-binding proteins. Physiol. Rev., 81, 153-208 https://doi.org/10.1152/physrev.2001.81.1.153
  32. Thrasher, J.D., Broughton, A. and Madison, R. (1990). Immune activation and autoantibodies in humans with long-term inhalation exposure to formaldehyde. Arch. Environ. Health, 45, 217-223 https://doi.org/10.1080/00039896.1990.9940805
  33. Zhong, W. and Que Hee, S.S. (2004). Formaldehyde-induced DNA adducts as biomarkers of in vitro human nasal epithelial cell exposure to formaldehyde. Mutat. Res., 563, 13-24 https://doi.org/10.1016/j.mrgentox.2004.05.012