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BOR - Papers in Press, published online ahead of print May 28, 2003.
Biol Reprod 2003, 10.1095/biolreprod.103.016261
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BIOLOGY OF REPRODUCTION 69, 1150–1157 (2003)
DOI: 10.1095/biolreprod.103.016261
© 2003 by the Society for the Study of Reproduction, Inc.

Toxicology

Numerical Chromosomal Abnormalities in Rat Epididymal Spermatozoa Following Chronic Cyclophosphamide Exposure1

Tara S. Barton3, Andrew J. Wyrobek5, Francesca S. Hill5, Bernard Robaire3,4, and Barbara F. Hales2,3

Departments of Pharmacology and Therapeutics3 Obstetrics and Gynecology,4 McGill University, Montreal, Quebec, Canada H3G 1Y6 Biology & Biotechnology Research Program,5 Lawrence Livermore National Laboratory, Livermore, California 94550

Chronic, low-dose treatment of male rats with cyclophosphamide, a chemotherapeutic agent, is known to affect progeny outcome adversely in a dose-dependent and time-specific manner, resulting in increased pre- and postimplantation loss as well as malformations. Concern exists regarding the genetic quality of mature gametes exposed to cyclophosphamide during mitosis and meiosis. The goal of the present study was to determine the effect of chronic cyclophosphamide treatment during spermatogenesis on the frequency of numerical chromosomal anomalies in epididymal spermatozoa. Male rats were treated with either saline or cyclophosphamide (6 mg kg-1 day-1) for 6 or 9 wk, and cauda epididymal spermatozoa were collected. The rat sperm Y-4 fluorescence in situ hybridization assay was used to assess the induction of spermatozoal disomy, nullisomy, and diploidy involving chromosomes Y and 4. The overall frequency of numerically abnormal spermatozoa was elevated approximately 2-fold (P < 0.001) after 9 wk of cyclophosphamide treatment. Exposure for 9 wk, but not for 6 wk, significantly increased the frequency of spermatozoa with chromosome 4 disomy (P < 0.02) and nullisomy (P < 0.05), but disomy Y and diploidy were not significantly increased with treatment compared to corresponding controls. Independent of treatment, only 27% of aneuploid spermatozoa presented with morphological abnormalities, but all diploid spermatozoa were approximately twice the size of normal cells. Thus, cyclophosphamide disrupts meiotic events before pachynema during spermatogenesis, emphasizing the potential for adverse progeny outcomes following genotoxic damage.

1 Supported by the Canadian Institutes of Health Research grant MOP-10462. The efforts of the Lawrence Livermore National Laboratory collaborators were performed under the auspices of the U.S. Department of Energy, under contract W-405-ENG-48, with funding support from NIEHS IAG Y01-ES-8016 and NIH superfund P42 ES04705.

2 Correspondence: B.F. Hales, Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec, Canada H3G 1Y6. FAX: 514 398 7120; bhales{at}pharma.mcgill.ca






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