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Hum. Reprod. Advance Access published online on November 25, 2005
Human Reproduction, doi:10.1093/humrep/dei416
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© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 31, 2005
Revised October 17, 2005
Accepted November 4, 2005

Article

Etoposide induces chromosomal abnormalities in mouse spermatocytes and stem cell spermatogonia

Francesco Marchetti 1 *, Francesca S. Pearson 1, Jack B. Bishop 2, and Andrew J. Wyrobek 1

1 Biosciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550
2 National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA

* To whom correspondence should be addressed.
Francesco Marchetti, E-mail: marchetti2{at}llnl.gov


  Abstract

BACKGROUND: Etoposide (ET) is a chemotherapeutic agent widely used in the treatment of leukaemia, lymphomas and many solid tumours such as testicular and ovarian cancers, all of which are common in patients of reproductive age. The purpose of the study was to characterize the long-term effects of ET on male germ cells using sperm fluorescence in situ hybridization (FISH) analyses. METHODS: Chromosomal aberrations (partial duplications and deletions) and whole chromosomal aneuploidies were detected in sperm of mice treated with a clinical dose of ET. Semen samples were collected at 25 and 49 days after dosing to investigate the effects of ET on meiotic pachytene cells and spermatogonial stem-cells, respectively. RESULTS: ET treatment resulted in major increases in the frequencies of sperm-carrying chromosomal aberrations in both meiotic pachytene (27- to 578-fold) and spermatogonial stem-cells (8- to 16-fold), but aneuploid sperm were induced only after treatment of meiotic cells (27-fold) with no persistent effects in stem cells. CONCLUSION: These results show that ET may have long-lasting effects on the frequencies of sperm with structural aberrations. This has important implications for cancer patients undergoing chemotherapy with ET because they may remain at higher risk for abnormal reproductive outcomes long after the end of chemotherapy.

Keywords: aneuploidy/chemotherapy/FISH/male germ cells/structural aberrations.
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