Paternal cyclophosphamide exposure exerts deleterious effects on early rat embryo development

Cyclophosphamide is an alkylating agent which has deleterious effects on reproduction in both males and females. When administered to male rats in chronic low doses (6 mg/kg/day), cyclophosphamide caused a dose-dependent increase in post-implantation death of the offspring. On day 7 of gestation, two days after implantation, the inner cell mass-derived embryonic tissues were retarded or absent while trophectoderm-derived extraembryonic tissues appeared normal. The preimplantation growth of embryos sired by cyclophosphamide-treated males was affected; as early as day 3 there was a significant decrease in cell number and in DNA synthesis. On day 3, there was no ultrastructural evidence of active cell death, and embryos underwent compaction, despite their decreased cell numbers. On day 4, embryos sired by treated males had less than half the cell number of controls: this decrease was not lineage-specific. A minority of embryos sired by treated males did not cavitate and showed signs of autophagic death on day 4 of gestation. The majority of embryos sired by treated males were able to cavitate and differentiate morphologically to form small blastocysts. Thus the target of cyclophosphamide damage may be a paternal gene more important for cell proliferation than for cell differentiation in the preimplantation rat embryo