Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm

Nature Genetics volume 16, pages 74–78 (1997)Cite this article

Abstract

Each year more than 20,000 children and young persons of reproductive age are exposed to known mutagens in the form of chemo- and/or radiotherapy for cancer in the States1,2. As more of these treatments are effective there is growing concern that genetic defects are introduced in the germ cells of these young patients. It is well documented for male rodents that treatment with chemo- and radio-therapeutic agents before mating can cause genetic damage in the germ line3–10, and the magnitude of heritable effects depends on the spermatogenic celt stage treated. Similar germinal effects are suspected to occur in humans but remain unproven11–15. Hodgkin's disease (HO) is an example of a malignancy which is typically diagnosed during a patient's reproductive years. In our study we observed eight male HD patients who were treated with NOVP (Novanthrone, Oncovin, Vinblastine, Prednisone) chemotherapy. We evaluated sperm aneuploidy using multi-colour fluorescence in situ hybridization (FISH)/and found ∼5-fold increases in sperm with disomies, diploidies and complex genotypes involving chromosome XfY and 8. Increases in sex chromsome aneuploidies arose from segregation errors at meiosis I as well as meiosis II. The aneuploidy effects were transient, however, declining to pretreatment levels within approximately 100 days after the end of the therapy. When compared with normal men, some HD patients showed higher proportions of certain sperm aneupolidy types even before their first therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Cancer Facts and Figures-1993. 1–27 (American Cancer Society, Atlanta Georgia, 1993).

  2. SEER Cancer Statistics Review:1973–1990(eds.Miller, B.A. et al.) 1.5-1.21,1.25,1.42,1.45, 11.51, XXIV.1-XXIV.13, XXVII. 1-XXVII. 15 (National Cancer Institute, NIH Pub. No. 93–2789,1993).

  3. Chandley, A.C. & Speed, R.M. Testing for nondisjunction in the mouse. Environ. Health Persp. 31, 123–129 (1979).

    Article  CAS  Google Scholar 

  4. Meistrich, M.L., Finch, M., da Cunha, M.F., Hacker, U. & Au, W. Damaging effects of fourteen chemotherapeutic drugs on mouse testis cells. Cancer Res. 42, 122–131 (1982).

    CAS  PubMed  Google Scholar 

  5. Russell, L.B. & Shelby, M.D. Tests for heritable genetic damage and for evidence of gonadal exposure in mammals. Mutat. Res. 154, 69–84 (1985).

    Article  CAS  Google Scholar 

  6. Lahdetie, J. Induction and survival of micronuclei in rat spermatids. Comparison of two meiotic micronudeus techniques using cyclophosphamide. Mutat. Res. 203, 47–53 (1988).

    Article  CAS  Google Scholar 

  7. Russell, L.D. & Russell, J.A. Short-term morphological response of the rat testis to administration of five chemotherapeutic agents. Am. J. Anat. 192, 142–68 (1991).

    Article  CAS  Google Scholar 

  8. Adler, I.-D. Synopsis of the in vivo results obtained with the 10 known or suspected aneugens tested in the CEC collaborative study. Mutat. Res. 287, 131–137 (1993).

    Article  CAS  Google Scholar 

  9. Kelly, S.M., Robaire, B. & Hales, B.F. Paternal cyclophosphamide exposure causes decreased cell proliferation in cleavage-stage embryos. Biol. Reprod. 50, 55–64 (1994).

    Article  CAS  Google Scholar 

  10. Generoso, W.M. et al. Dominant lethal and heritable translation tests with chlorambucil and melphalan in male mice. Mutat. Res. 345, 167–180 (1995).

    Article  CAS  Google Scholar 

  11. Li, F., Fine, W., Jaffe, N., Holmes, G.E. & Holmes, F.F. Offspring of patients treated for cancer in childhood. J. Natl. Cancer Inst. 62, 1193–1197 (1979).

    CAS  PubMed  Google Scholar 

  12. Mulvihill, J.J. Sentinel and other mutational effects in offspring of cancer survivors. Mutat Environ. PartC, 179–186 (1990).

    Google Scholar 

  13. Nygaard, R. et al. Reproduction following treatment for childhood leukemia: a population-based prospective cohort study of fertility and offspring. Med. Pediat. Oncol. 19, 459–466 (1991).

    Article  CAS  Google Scholar 

  14. Nicholson, H.S., Mulvihill, J.J. & Byrne, J. Late effects of therapy in adult survivors of osterosarcoma and Ewing's sarcoma. Med. Pediatr. Oncol. 20, 6–12 (1992).

    Article  CAS  Google Scholar 

  15. Senturia, Y.D., Peckham,, C.S., Peckham, M.J. Children fathered by men treated for testicular cancer. Lancet 2, 766–769 (1985).

    Article  CAS  Google Scholar 

  16. Hassold, T.J. & Jacobs, P.A. Trisomy in man. Ann. Rev. Genet. 18, 69–97 (1984).

    Article  CAS  Google Scholar 

  17. Jacobs, P.A. et al. Klinefelter's syndrome: an analysts of the origin of the additional sex chromosome using molecular probes. Ann. Hum. Genet. 52, 93–109 (1988).

    Article  CAS  Google Scholar 

  18. Hassold, T., Pettay, D., May, K. & Robinson, A. Analysis of nondysjunction in sex chromosome tetrasomy and pentasomy. Hum. Genet. 85, 648–650 (1990).

    Article  CAS  Google Scholar 

  19. Jacobs, P.A. The chromosome complement of human gametes, in Oxford Reviews of Reproductive Biology, vol. 14 (ed Milligan S.R.) 47–72 (Oxford University Press, New York, 1992).

    Google Scholar 

  20. Lorda-Sanchez, I., Binkert, F.M. & Schinzel, A. Molecular study of 45, X conceptuses: correlation with clinical findings. Am. J. Med. Genet. 42, 487–490 (1992).

    Article  CAS  Google Scholar 

  21. Bishop, J.B. et al. Aneuploidy in germ cells: Etiologies and risk factors. Environ. Mol. Mutag. 28, 159–166 (1996).

    Article  CAS  Google Scholar 

  22. Hagemeister, F.B. et al. Treatment of early stages of Hodgkin's disease with novantrone, vincristine, vinblastine, prednisone and radiotherapy. Semin. Hematol. 31, Suppl 36–43 (1994).

    CAS  PubMed  Google Scholar 

  23. Robbins, W.A. et al. Three-probe fluorescence in situ hybridization to assess chromosome X, Y, 8 aneuploidy in sperm of 14 men from two healthy groups: preliminary evidence for an age effect. Reprod. Fertil. Develop. 7, 799–809 (1995).

    Article  CAS  Google Scholar 

  24. Wyrobek, A.J., Alhborn, T., Balhorn, R., Stanker, L. & Pinkel, D. Fluorescence in situ hybridization to Y chromosomes in decondensed human sperm nuclei. Mol. Reprod. Dev. 27, 200–208 (1990).

    Article  CAS  Google Scholar 

  25. Robbins, W.A., Segraves, R., Pinkel, D. & Wyrobek, A.J. Detection of aneuploid human sperm by fluorescence in situ hybridization: Evidence for a donor difference in frequency of sperm disomk for chromosomes 1 and Y. Am. J. Hum. Genet. 52, 799–807 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wyrobek, A.J., Robbins, W.A., Mehraein, Y., Pinkel, D. & Weier, H-U. Detection of sex-chromosomal aneuploidies X-X, Y-Y, and X-Y in human sperm using two-chromosome fluorescence in situ hybridization. Am. J. Med. Genetics. 53, 1–7 (1994).

    Article  CAS  Google Scholar 

  27. Brandriff, B. & Gordon, L. Human sperm cytogenetics and one-cell zygote. in Biology of Mammalian Germ Cell Mutagenesis Banbury ♯34: (eds Alien J., Lyon, M.F., Moses, MJ. & Russell, L.B.) 83–194 (Cold Spring Harbor Laboratory Press, 1990).

    Google Scholar 

  28. Griffin, O.K. et al. Nondisjunction studies of human sperm: evidence for a paternal age effect on trisomy. Hum. Mol. Gene. 4, 2227–2232 (1995).

    Article  CAS  Google Scholar 

  29. Martin, R.H. et al. An increased frequency of human sperm chromosomal abnormalities after radiotherapy. Mutat. Res. 174, 219–225 (1986).

    Article  CAS  Google Scholar 

  30. Martin, R.H. et al. A comparison of chromosomal aberrations induced by in vivo radiotherapy in human sperm and lymphocytes. Mutat. Res. 226, 21–30 (1989).

    Article  CAS  Google Scholar 

  31. Genesca, A. et al. Significance of structural chromosome aberrations in human sperm: analysis of induced aberrations. Hum. Genet. 85, 495–499 (1990).

    Article  CAS  Google Scholar 

  32. Jenderny, J., Jacobi, M.L., Ruger, A. & Rohrborn, G. Chromosome aberrations in 450 sperm complements from eight controls and lack of increase after chemotherapy in two patients. Hum. Genet. 90, 151–154 (1992).

    CAS  PubMed  Google Scholar 

  33. Brandriff, B.F., Meistrich, M.L., Gorden, LA.,, Carrano, A.V. & Liang,, J.C. Chromosomal damage in sperm of patients surviving Hodgkin's disease following MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) therapy with and without radiotherapy. Hum. Genet. 93, 295–299 (1994).

    Article  CAS  Google Scholar 

  34. Martin, R.H., Rademaker, A.W. & Jeonard, N.J. Analysis of chromosomal abnormalities in human sperm after chemotherapy by karyotyping and fluorescence in situ hybridization (FISH) Cancer Genet. Cytogenet. 80, 29–32 (1995).

    Article  CAS  Google Scholar 

  35. Hagemeister, F.B. Are alkylating agents a necessary component in the therapy of Hodgkin's disease. Leuk. Lymphoma 10, 91–97 (1993).

    Article  Google Scholar 

  36. Liang, J.C. et al. A new chemotherapy regimen for treatment of Hodgkin's disease associated with minimal genotoxicity. Leuk. Lymphoma 9, 503–508 (1993).

    Article  CAS  Google Scholar 

  37. Meistrich, M.L. Potential genetic risks of using semen collected during chemotherapy. Hum. Reprod. 8, 8–10 (1993).

    Article  CAS  Google Scholar 

  38. Carson, S.A., Gentry, W.L., Smith, A.L. & Buster, J.E. Feasibility of semen collection and cryopreservation during chemotherapy. Hum. Reprod. 6, 992–994 (1991).

    Article  CAS  Google Scholar 

  39. Meistrich, M.L., Vassilopoulou-Sellin, R. & Lipshultz, L.I. Adverse effects of treatment: gonadal dysfunction. in Principles and Practices of Oncology. 5th edn. (eds Devita, V.T., Hellman, S. & Rosenberg, S.A.) (J.B. Lippincott Co.,Philadelphia, in the press).

  40. Wyrobek, A.J. Methods and concepts in detecting abnormal reproductive outcomes of paternal origin. J. Reprod. Toxicol. 7, 3–16 (1993).

    Article  Google Scholar 

  41. Van Hummelen, P., Lowe, X.R. & Wyrobek, A.J. Simultaneous detection of structural and numerical chromosomal abnormalities in spem of healthy men by multi-color FISH. Hum. Genet. 98, 608–615 (1996).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California, 94551, USA

    Wendie A. Robbins, Dan Moore, Michael J. Cassel & Andrew J. Wyrobek

  2. School of Public Health,Epidemiology Group, University of California at Berkeley, Berkeley, California, 94720, USA

    Wendie A. Robbins & Brenda Eskenazi

  3. Department of-Experimental Radiation Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Marvin L. Meistrich & Gene Wilson

  4. Department of Hematology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Fredrick B. Hagemeister

  5. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, 94720, USA

    Heinz-Ulrich Weier

Authors
  1. Wendie A. Robbins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marvin L. Meistrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dan Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fredrick B. Hagemeister
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Heinz-Ulrich Weier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael J. Cassel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gene Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Brenda Eskenazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrew J. Wyrobek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew J. Wyrobek.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robbins, W., Meistrich, M., Moore, D. et al. Chemotherapy induces transient sex chromosomal and autosomal aneuploidy in human sperm. Nat Genet 16, 74–78 (1997). https://doi.org/10.1038/ng0597-74

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0597-74

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing