Persistent DDT metabolite p,p'–DDE is a potent androgen receptor antagonist

Nature volume 375, pages581–585(1995)Cite this article

Abstract

THE increase in the number of reports of abnormalities in male sex development in wildlife and humans coincided with the introduction of 'oestrogenic' chemicals such as DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane) into the environment. Although these phenotypic alterations are thought to be mediated by the oestrogen receptor, they are also consistent with inhibition of androgen receptor-mediated events. Here we report that the major and persistent DDT metabolite,P,P′-DDE (l,l-dichloro-2,2-bis(P- chlorophenyl)ethylene), has little ability to bind the oestrogen receptor, but inhibits androgen binding to the androgen receptor, androgen-induced transcriptional activity, and androgen action in developing, pubertal and adult male rats. The results suggest that abnormalities in male sex development induced by P,P′-DDE and related environmental chemicals may be mediated at the level of the androgen receptor.

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References

  1. 1

    Sharpe, R. M. & Skakkebaek, N. E. Lancet 341, 1392–1395 (1993).

    CAS  Article  Google Scholar 

  2. 2

    Carlson, E., Giwercman, A., Keiding, N. & Skakkebaek, N. Br. med. J. 305, 609–612 (1992).

    Article  Google Scholar 

  3. 3

    Nelson, J. A. Biochem. Pharmacol. 23, 447–451 (1974).

    CAS  Article  Google Scholar 

  4. 4

    Robison, A. K., Schmidt, W. A. & Stancel, G. M. J. Tox. envir. Hlth 16, 493–508 (1985).

    CAS  Google Scholar 

  5. 5

    Welch, R. M., Levin, W. & Conney, A. H. Tox. appl. Pharmac. 14, 358–367 (1969).

    CAS  Article  Google Scholar 

  6. 6

    Gellert, R. J., Heinrichs, W. L. & Swerdloff, R. S. Endocrinology 91, 1095–1100 (1972).

    CAS  Article  Google Scholar 

  7. 7

    Clemens, L. G., Gladue, B. A. & Coniglio, L. P. Horm. Behav. 10, 40–53 (1978).

    CAS  Article  Google Scholar 

  8. 8

    Neumann, F. et al. Recent Prog. Horm. Res. 26, 337–410 (1970).

    CAS  PubMed  Google Scholar 

  9. 9

    Wilson, E. M. & French, F. S. J. biol. Chem. 251, 5620–5629 (1976).

    CAS  PubMed  Google Scholar 

  10. 10

    Kelce, W. R., Monosson, E., Gamcsik, M. P., Laws, S. C. & Gray, L. E. Tox. appl. Pharmac. 126, 276–285 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Morgan, D. P. & Roan, C. C. Archs. envir. Hlth 22, 301–308 (1971).

    CAS  Article  Google Scholar 

  12. 12

    Dustman, E. H. & Stickel, L. F. Ann. N.Y. Acad. Sci. 160, 162–172 (1969).

    ADS  CAS  Article  Google Scholar 

  13. 13

    Bitman, J. & Cecil, H. C. J. agric. Fd Chem. 18, 1108–1112 (1970).

    CAS  Article  Google Scholar 

  14. 14

    Nelson, J. A. Biochem. Pharmacol. 23, 447–451 (1974).

    CAS  Article  Google Scholar 

  15. 15

    Nelson, J. A., Struck, R. F. & James, R. J. Tox. envir. Hlth 4, 325–339 (1978).

    CAS  Article  Google Scholar 

  16. 16

    Zhou, Z.-X., Sar, M., Simental, J. A., Lane, M. V. & Wilson, E. M. J. biol. Chem. 269, 13115–13123 (1994).

    CAS  PubMed  Google Scholar 

  17. 17

    Imperato-McGinley, J., Sanchez, R. S., Spencer, J. R., Yee, B. & Vaughan, E. D. Endocrinology 131, 1149–1156 (1992).

    CAS  Article  Google Scholar 

  18. 18

    Dürnberger, H. & Kratochwil, K. Cell 19, 465–471 (1980).

    Article  Google Scholar 

  19. 19

    Korenbrot, C. C., Huhtaniemi, I. T. & Weiner, R. I. Biol. Reprod. 17, 298–303 (1977).

    CAS  Article  Google Scholar 

  20. 20

    Gray, L. E., Ostby, J. M. & Kelce, W. R. Tox. appl. Pharmac. 129, 46–52 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Kupfer, D. CRC Crit. Rev. Tox. 4, 83–124 (1975).

    CAS  Article  Google Scholar 

  22. 22

    Stone, C. R., Gray, L. E. Jr, Roberts, K. P. & Kelce, W. R. J. Androl. 16 (suppl.), 42 (1995).

    Google Scholar 

  23. 23

    Leger, J. G., Guellecand, R. L. & Tenniswood, M. P. R. The Prostate 13, 131–142 (1988).

    CAS  Article  Google Scholar 

  24. 24

    Page, M. J. & Parker, M. G. Molec. cell. Endrocrin. 27, 343–355 (1982).

    CAS  Article  Google Scholar 

  25. 25

    Guillette, L. J. Jr et al. Envir. Hlth Perspect. 102, 680–688 (1994).

    CAS  Article  Google Scholar 

  26. 26

    Bouwman, H., Cooppan, R. M., Becker, P. J. & Ngxongo, S. J. Tox. Envir. Hlth 33, 141–155 (1991).

    CAS  Article  Google Scholar 

  27. 27

    Curley, A., Copeland, M. F. & Kimbrough, R. D. Archs. envir. Hlth 19, 628–632 (1969).

    CAS  Article  Google Scholar 

  28. 28

    Wooley, D. E. & Talens, G. M. Tox. appl. Pharmac. 18, 907–916 (1971).

    Article  Google Scholar 

  29. 29

    Kelce, W. R. & Ganjam, V. K. Steroids 52, 217–235 (1988).

    CAS  Article  Google Scholar 

  30. 30

    Simental, J. A., Sar, M., Lane, M. V., French, F. S. & Wilson, E. M. J. biol. Chem. 266, 510–518 (1991).

    CAS  PubMed  Google Scholar 

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Affiliations

  1. Reproductive Toxicology Branch, Developmental Toxicology Division, Health Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina, 27711, USA

    William R. Kelce, Christy R. Stone, Susan C. Laws & L. Earl Gray

  2. The Laboratories for Reproductive Biology and the Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina, 27599, USA

    Jon A. Kemppainen & Elizabeth M. Wilson

  3. Departments of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, 27599, USA

    Elizabeth M. Wilson

Authors
  1. William R. Kelce
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  2. Christy R. Stone
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  3. Susan C. Laws
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  4. L. Earl Gray
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  5. Jon A. Kemppainen
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  6. Elizabeth M. Wilson
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Kelce, W., Stone, C., Laws, S. et al. Persistent DDT metabolite p,p'–DDE is a potent androgen receptor antagonist. Nature 375, 581–585 (1995). https://doi.org/10.1038/375581a0

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