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A transgenic mouse model for the detection of cellular stress induced by toxic inorganic compounds

Nature Biotechnology volume 15, pages 1392–1397 (1997)Cite this article

Abstract

Transgenic mice for genotoxicity testing have been developed, although no such models have been produced for the evaluation of toxic, nongenotoxic chemical compounds. We have developed a transgenic mouse model for the analysis of toxic inorganic compounds. We engineered a mouse lineage with the human growth hormone (hGH) gene under the control of the human hsp70 promoter, in which a plasma-detectable hGH response can be elicited by exposure to heat shock. In primary cell cultures from these mice, hGH release was observed following treatment with several toxic inorganics. Transgenic mice injected intraperitoneally with sodium arsenite, cadmium chloride, copper sulphate, or methylmer-curium chloride showed significant hGH levels in plasma.

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References

  1. Jaenisch, R. 1988. Transgenic animals. Science 240: 1468–1474.

    Article  CAS  Google Scholar 

  2. Merlino, G.T. 1991. Transgenic animals in biomedical research. FASEB J 5: 2996–3001.

    Article  CAS  Google Scholar 

  3. Bradley, A., Hasty, P., Davis, A. and Ramirez-Soli, R. 1992. Modifying the mouse: design and desire. Biotechnology 10: 534–539.

    CAS  Google Scholar 

  4. Gossen, J.A., De Leeuw, W.J.F., Tan, C.H.T., Zwarthoff, E.C., Berends, R., Knook, D.L. et al. 1989. Efficient rescue of integrated shuttle vectors from transgenic mice: a model for studying mutations in vivo. Proc. Natl. Acad. Sci. USA 86: 7971–7975.

    Article  CAS  Google Scholar 

  5. Kohler, S.W., Provost, G.S., Reck, A., Kretz, P.L., Bullock, W.O., Sorge, J.A. et al. 1991. Spectra of spontaneous and mutagen-induced mutations in the Lad gene in transgenic mice. Proc. Natl. Acad. Sci. USA 88: 7958–7862.

    Article  CAS  Google Scholar 

  6. Douglas, G.R., Jiao, J., Gingerich, J.D., Gossen, J.A. and Soper, L.M. 1995. Temporal and molecular characteristics of mutations induced by ethylnitrosourea in germ cells isolated from seminiferous tubules and in spermatozoa of lacZ transgenic mice. Proc. Natl. Acad. Sci. USA 92: 7485–7489.

    Article  CAS  Google Scholar 

  7. Boerrigter, M.E.T.I., Dollè, M.E.T., Martus, H.J., Gossen, J.A. and Viij, J. 1995. Plasmid-based transgenic mouse model for studying in vivo mutations. Nature 377: 657–659.

    Article  CAS  Google Scholar 

  8. Gossen, J.A. and Vijg, J. 1993. Transgenic mice as model systems for studying gene mutations in vivo. Trends Genet. 9: 27–31.

    Article  CAS  Google Scholar 

  9. Albertini, R.J. 1994. Why use somatic mutations for human biomonitoring? Env. Mol. Mutagen. 23(Suppl 24): 18–22.

    Article  Google Scholar 

  10. Goldsworthy, T.L., Recio, L., Brown, K., Donehower, L.A., Mirsalis, J.C., Tennant, R.W. et al. 1994. Transgenic animals in toxicology. Fundam. Appl. Toxicol. 22: 8–19.

    Article  CAS  Google Scholar 

  11. Nover, L. 1987. Expression of heat shock genes in homologous and heterologous systems. Enzyme Microb. Technol. 9: 129–144.

    Article  Google Scholar 

  12. Hightower, L.E. and Ryan, J.A. 1997. Are stress proteins part of a cell's solution to toxicity or are they part of the problem? Hepatology 25: 1279–1281.

    Article  CAS  Google Scholar 

  13. Huggett, R.J., Kimerle, R.A., Mehrle, P.M., and Bergman, H.L. 1992. Biomarkers: biochemical, physiological and histological markers of anthropogenic stress. Lewis Publishers, Boca Raton, FL.

    Google Scholar 

  14. Dreano, M., Brochot, J., Myers, A., Cheng-Myers, A., Rungger, D., Voellmy, R. et al. 1986. High-level, heat-regulated synthesis of proteins in eukaryotic cells. Gene 49: 1–8.

    Article  CAS  Google Scholar 

  15. Dreano, M., Fischbach, M., Montandon, F., Salina, C., Padieu, P. and Bromley, P. 1988. Production of secretable proteins using the passage in vivo as tumors of cells carrying heat-inducible expression constructs. Biotechnology 6: 953–958.

    CAS  Google Scholar 

  16. Fischbach, M., Sabbioni, E. and Bromley, P. 1993. Induction of the human growth hormone gene placed under human hsp70 promoter control in mouse cells: a quantitative indicator of metal toxicity. Cell Biol. Toxicol. 9: 177–188.

    Article  CAS  Google Scholar 

  17. Levinson, W., Opperman, H. and Jackson, J. 1980. Transition series metals and sulfhydril reagents induce the synthesis of four proteins in eukaryotic cells. Biochem. Biophys. Ada. 606: 170–180.

    CAS  Google Scholar 

  18. Honda, K., Hatayama, T., Takahashi, K. and Yukioka, M. 1992. Heat shock proteins in human and mouse embryonic cells after exposure to heat shock or teratogenic agents. Teratog. Carcinog. Mutagen. 11: 235–244.

    Article  Google Scholar 

  19. Goehring, P.L., Fisher, B.R., Chaudary, P.P. and Dick, C.A. 1992. Relationship between stress protein induction in rat kidney by mercuric chloride and nephro-toxicity. Toxicol. Appl. Pharmacol. 113: 184–191.

    Article  Google Scholar 

  20. Goehring, P.L., Fisher, B.R. and Kish, C.L. 1993. Stress protein synthesis induced in rat liver by cadmium precedes hapatotoxicity. Toxicol. Appl. Pharmacol. 122: 139–148.

    Article  Google Scholar 

  21. Ovelgonne, H.H., Wiegant, F.A.C., Souren, J.E.M., van Rijn, H., and van Wijk, R. 1995. Enhancement of the stress response by low concentrations or arsenite in arsenite-pretreated Reuber H35 hepatoma cells. Toxicol. Appl. Pharmacol. 132: 146–155.

    Article  CAS  Google Scholar 

  22. Ovelgonne, H.H., Souren, J.E.M., Wiegant, F.A.C. and van Wijk, R. 1995. Relationship between cadmium-induced expression of heatshock genes, inhibition of protein synthesis and cell death. Toxicology 99: 19–30.

    Article  CAS  Google Scholar 

  23. Salminen, W.F., Voellmy, R. and Roberts, S.M. 1996. Induction of hsp in HepG2 cells in response to hepatotoxicants. Toxicol. Appl. Pharmacol. 141: 117–123.

    Article  CAS  Google Scholar 

  24. Richardson, M.L. L. (ed.). 1993. The dictionary of substances and their effects. The Royal Society of Chemistry, Cambridge, see compounds listed in alphabetical order).

    Google Scholar 

  25. Aresini, G., Karcher, W., Roi, R. and Sevilla-Marcos, J.M. 1995. Data profiles for selected chemical series. Report EUR 16248 EN.

  26. Plunket, E.R. 1987. Handbook of industrial toxicology. Chemical Publishing Co. Inc., New York.

    Google Scholar 

  27. Roush, W. 1996. Hunting for animal alternatives. Science 274: 168–171.

    Article  CAS  Google Scholar 

  28. Dreano, M., Marq, J.B. and Bromley, B.R. 1988. Antibody formation against heat-induced gene products expressed in animals. Biotechnology 6: 1340–1343.

    CAS  Google Scholar 

  29. Festing, M.F.W. 1997. Fat rats and carcinogenesis screening. Nature 388: 321–322.

    Article  CAS  Google Scholar 

  30. Hogan, B., Costantini, F. and Lacy, E. 1986. Manipulating the mouse embryo: a laboratory manual.Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

    Google Scholar 

  31. Sambrook, J., Fritsch, E.R. and Maniatis, T. 1989. Molecular cloning: a laboratory manual.Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.

    Google Scholar 

  32. Innis, M.A., Gelfand, D.H., Sninsky, J.J. and White, T.J. 1990. PCR protocols: a guide to methods and applications. Academic Press, New York.

    Google Scholar 

  33. Robertson, E.J., 1987. pp.77–88 in Teratocarcinomas and embryonic stem cells: a practical approach.IRL Press, Oxford, UK.

    Google Scholar 

  34. Clerici, L., Sacco, M.G. and Merlini, M. 1989. Acetaldehyde activation of poly(ADP-ribose) polymerase in hepatocytes of mice treated in vivo. Mut Res. 227: 47–51.

    Article  CAS  Google Scholar 

  35. Campbell, J.A., Eppersimons, C.R., Kligerman, A.D., Petro, A.R., Sharief, Y. and Allen, J.W. 1986. Sister cromatid exchange analysis in cultured primary lung, liver and kidney cells of mice following in vitro exposure to vinyl carbamate. In Vitro Cell Dev. Biol. 22: 443–448.

    Article  CAS  Google Scholar 

  36. Dexter, T.M., Allen, T.D. and Lajta, L.G. 1977. Conditions controlling the proliferation of hemopoietic stem cells in vitro. J. Cell Physiol. 91: 335–339.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Advanced Biomedical Technologies, National Research Council, via Ampere 56, 20131, Milan, Italy

    Maria Grazia Sacco, Luigi Zecca, Luca Bagnasco, Peter Bromley, Enrica Mira Catò, Romeo Roncucci & Paolo Vezzoni

  2. Institute of Pharmacological Sciences, via Balzaretti 9, 20131, Milan, Italy

    Giulia Chiesa & Cinzia Parolini

  3. Joint Research Center, Environmental Institute, Environmental Toxicology and Human Health Unit, 21020, Ispra, Italy

    Libero A. Clerici

Authors
  1. Maria Grazia Sacco
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  2. Luigi Zecca
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  3. Luca Bagnasco
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  4. Giulia Chiesa
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  6. Peter Bromley
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  9. Libero A. Clerici
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  10. Paolo Vezzoni
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Sacco, M., Zecca, L., Bagnasco, L. et al. A transgenic mouse model for the detection of cellular stress induced by toxic inorganic compounds. Nat Biotechnol 15, 1392–1397 (1997). https://doi.org/10.1038/nbt1297-1392

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  • DOI: https://doi.org/10.1038/nbt1297-1392

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