INDUCTION OF MEIOTIC MATURATION IN-VIVO IN THE MOUSE BY IMP DEHYDROGENASE INHIBITORS - EFFECTS ON THE DEVELOPMENTAL CAPACITY OF OVA

The present study was conducted to examine the effects of priming dura tion and inosine monophosphate (IMP) dehydrogenase inhibitors on the f ertilization and pre- and postimplantation development of ova from imm ature 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 day s 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 cult ured in Whitten's medium. Some mice were not killed until 7 or 19 d po stvaginal plug to determine the extent of implantation or development to term, respectively. In superovulated control mice, 94% of ova devel oped 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 m ice (83%) had term embryos (11/mouse). Induction of meiotic maturation with Mt or MA after 1 d of priming, followed 1 d later by hCG injecti on and mating, resulted in a significant loss of preimplantation devel opmental capacity (20-22% two-cells; 29-50% blastocysts). These number s were similar whether or not the mice were mated, indicating that the development was parthenogenetic. In addition, Mz treatment reduced th e number of mice with implantion 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, m ost of the implanted embryos were resorbed after implantation. This ef fect could be attributed, in part, to each of the following: (1) parth enogenetic activation; (2) aging of the metaphase II oocyte before ins emination; 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 dehydr ogenase inhibitors. These data show that induction of premature meioti c maturation by IMP dehydrogenase inhibitors results in a significant loss of developmental capacity and indicates that active purine metabo lic pathways in situ maintain meiotic arrest acid prevent premature me iotic maturation that would result in compromised development. (C) 199 4 Wiley-Liss, Inc.