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National Institute of Environmental Health Sciences

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Publication Detail

Title: Numerical chromosomal abnormalities in rat epididymal spermatozoa following chronic cyclophosphamide exposure.

Authors: Barton, Tara S; Wyrobek, Andrew J; Hill, Francesca S; Robaire, Bernard; Hales, Barbara F

Published In Biol Reprod, (2003 Oct)

Abstract: 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.

PubMed ID: 12773405 Exiting the NIEHS site

MeSH Terms: Animals; Chromosome Aberrations*; Cyclophosphamide/administration & dosage; Cyclophosphamide/toxicity*; Dose-Response Relationship, Drug; Epididymis/cytology; Epididymis/drug effects*; Epididymis/physiology; In Situ Hybridization, Fluorescence; Male; Mutagens/administration & dosage; Mutagens/toxicity*; Rats; Rats, Sprague-Dawley; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.; Spermatozoa/drug effects*; Spermatozoa/physiology; Y Chromosome

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