Biology of Reproduction, Vol 50, 55-64, Copyright © 1994 by Society for the Study of Reproduction

ARTICLES

Paternal cyclophosphamide exposure causes decreased cell proliferation in cleavage-stage embryos [published erratum appears in Biol Reprod 1994 Mar;50(3):711]

SM Austin, B Robaire, BF Hales and SM] Kelly SM [corrected to Austin
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.

Exposure of the male germ cell to cyclophosphamide during spermatogenesis and sperm maturation can interfere with development of the embryo. When male rats were treated with a chronic low dose of cyclophosphamide for 4 wk there was a dramatic increase in early postimplantation loss in their progeny, characterized by implantation sites selectively lacking in embryonic tissues. The present study was designed to determine the earliest appearance of a paternal effect of cyclophosphamide treatment and to examine whether the embryonic lineage was selectively affected. Male Sprague-Dawley rats were orally dosed for 4-5 wk with saline or 6 mg/kg per day of cyclophosphamide; their progeny were obtained on Days 2, 2.5, 3, 4, and 4.5 of gestation. Paternal cyclophosphamide treatment had no effect on the mean number of embryos per pregnant female. However, as early as Day 3 of gestation, there was a significant decrease in cell number among the embryos sired by cyclophosphamide-treated males, increasing to a greater than 50% decrease in cell number by Day 4. The cell doubling time in embryos sired by treated males (16 h) was longer than that of controls (12 h). This decreased proliferation rate was confirmed by a dramatic decrease in the capacity of both Day 3 and Day 4 embryos sired by cyclophosphamide-treated males to incorporate [3H]thymidine over a 26-h culture period. Cytogenetic analysis in a limited number of blastomeres entering metaphase revealed no evidence of chromosomal abnormalities. Both the trophectoderm and the inner cell mass cells were proportionally decreased in Day 4.5 embryos sired by cyclophosphamide- treated males. Thus, paternal cyclophosphamide exposure affected both cell lineages in the conceptus as early as Day 3 of gestation.

This article has been cited by other articles:

				W. Harrouk, B. Robaire, and B. F. Hales Paternal Exposure to Cyclophosphamide Alters Cell-Cell Contacts and Activation of Embryonic Transcription in the Preimplantation Rat Embryo Biol Reprod, July 1, 2000; 63(1): 74 - 81. [Abstract] [Full Text]