Impact of paternal exposure to chemotherapy on offspring in the rat.

Paternal exposure to chemotherapeutics may have adverse effects on offspring. In the rat, chronic low-dose paternal exposure to the anticancer drug cyclophosphamide increased pre- and postimplantation loss and malformations. The effects of paternal drug treatment on progeny were influenced by the stage when germ cells were first exposed. Chronic cyclophosphamide treatment resulted in a dramatic decrease in the expression of stress response genes in pachytene spermatocytes and round spermatids but not in elongated spermatids; reduced gene expression may allow damage to accumulate. Exposure for 9 weeks, but not for 6, increased the incidence of aneuploidy. DNA strand breaks were maximal 3 weeks after short-term or acute treatment, during spermiogenesis. Cyclophosphamide-exposed spermatozoa imparted DNA damage to the fertilized embryo. Total RNA synthesis was higher in one-cell embryos sired by drug-treated fathers than in controls, and the expression of specific genes was altered. Thus, in the rat, paternal exposure to an anticancer drug altered germ cell quality, disrupting embryo development and dysregulating zygotic gene activation.