Induction of meiotic maturation in vivo in the mouse by IMP dehydrogenase inhibitors: effects on the developmental capacity of ova.

Abstract

The present study was conducted to examine the effects of priming duration and inosine monophosphate (IMP) dehydrogenase inhibitors on the fertilization and pre- and postimplantation development of ova from immature mice. Mice were primed with equine chorionic gonadotropin (eCG) and 1 d later were treated with mycophenolic acid (MA) or mizoribine (Mz; also known as bredinin) or an equal volume of the vehicle. Two days after priming, mice received human chorionic gonadotropin (hCG) and were mated with fertile males. Some mice received hormone but were not mated. Ova were isolated from the oviducts 23-24 hr post-hCG and cultured in Whitten's medium. Some mice were not killed until 7 or 19 d postvaginal plug to determine the extent of implantation or development to term, respectively. In superovulated control mice, 94% of ova developed to two-cells and 82% of these progressed to the blastocyst stage. Nineteen of 23 mice (83%) had implantations (24/mouse) and 20 of 24 mice (83%) had term embryos (11/mouse). Induction of meiotic maturation with Mz or MA after 1 d of priming, followed 1 d later by hCG injection and mating, resulted in a significant loss of preimplantation developmental capacity (20-22% two-cells; 29-50% blastocysts). These numbers were similar whether or not the mice were mated, indicating that the development was parthenogenetic. In addition, Mz treatment reduced the number of mice with implantation sites (13 of 19, 68%), the number of implantations per mouse (10), the viability of the implantations, and development to term (four of 24, mice, 17%; one embryo/mouse). Thus, most of the implanted embryos were resorbed after implantation. This effect could be attributed, in part, to each of the following: (1) parthenogenetic activation; (2) aging of the metaphase II oocyte before insemination; and (3) resumption of meiotic maturation before the oocyte had reached its full developmental potential. Coincident gonadotropin injection reversed the loss of development brought about by IMP dehydrogenase inhibitors. These data show that induction of premature meiotic maturation by IMP dehydrogenase inhibitors results in a significant loss of developmental capacity and indicates that active purine metabolic pathways in situ maintain meiotic arrest and prevent premature meiotic maturation that would result in compromised development.