title: Association of cyclophosphamide-induced male-mediated, foetal abnormalities with reduced paternal germ-cell apoptosis.
abstract: To investigate the mechanism by which malformed offspring can result from the exposure of males to mutagens, we treated adult male rats with 0, 1.4, 3.4 or 5.1 mg/kg cyclophosphamide, 6 days per week for 9 weeks, a treatment regimen known to induce heritable abnormalities. Testis samples from some of the animals were then collected for fixation in Carnoy's fluid and subsequent analysis of germ-cell apoptosis and proliferation. The remainder were mated, resulting in a greater than 11-fold increase in the proportion of abnormal offspring produced in the 5.1 mg/kg group. The number of apoptotic cells per stage XII/XIII tubular cross-section decreased with increasing dose, significantly so at 5.1 mg/kg (P<0.05). No statistically significant effect was found on spermatocyte numbers at this dose, indicating that a reduction in the amount of cells available to undergo apoptosis cannot explain the decrease. The inappropriate survival of damaged germ-cells caused by a lowering of the incidence of apoptosis may, therefore, account for the rise in the proportion of foetal malformations.
authors.affiliation: Institute of Reproductive Medicine of the University, Domagkstrasse 11, D-48129, Münster, Germany.
authors.forename: M H
authors.initials: MH
authors.lastname: Brinkworth
authors.forename: E
authors.initials: E
authors.lastname: Nieschlag
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects*; D008297:Male; D009153:Mutagens / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D013090:Spermatocytes / Q000166:cytology / Q000187:drug effects*; D013737:Testis / Q000166:cytology / Q000187:drug effects
chemical_list: D009153:Mutagens; D003520:Cyclophosphamide