Molecular medical approaches for alleviating infertility and understanding assisted reproductive technologies

Fertilization is a precisely orchestrated cascade of events that results in the union of paternal and maternal genomes and in the establishment of mitotic potential of the zygote. To initiate embryonic development, the structures of the fertilizing sperm have to be disassembled and transformed into zygotic components by interactions with the cytoplasm of the egg. These interactions include the decondensation of the sperm nucleus into male pronucleus, the assembly of the zygotic centrosome, and the gathering of centrosomal proteins and sperm aster microtubules around the sperm centriole. Both the formation of the male pronucleus and the assembly of the zygotic centrosome are crucial steps required for pronuclear apposition and genomic union. The discovery of previously undetected fertilization failures that are due to defects in the assembly of the zygotic centrosome, abnormal pronuclear development, and compromised cytoskeletal dynamics enforces the development of new diagnostic strategies. Moreover, the introduction of new methods of infertility treatments, such as intracytoplasmic sperm injection and round spermatid nucleus injection into assisted human reproductive technology programs, emphasizes our lack of understanding of the cellular and molecular basis of human fertilization and evokes the need for additional experimentation. These efforts, however, are compromised by the sensitive nature of human embryo research and thus are severely restricted. Animal models that are reliable and cost-effective and that feature the characteristics of human fertilization have therefore been sought. Rodents such as the rat, mouse, and hamster are poor models owing to their maternal inheritance of the zygotic centrosome that is in strong contrast with the biparentally contributed assembly of the human zygotic centrosome during fertilization. Although rabbits are similar to humans from the standpoint of mitotic potential inheritance, information on postfertilization events in rabbits are lacking. Nonhuman primates represented by the rhesus monkey proved to be a reliable model for human in vitro fertilization and intracytoplasmic sperm injection, an advantage that is further emphasized by phyllogenetic similarity. In situations in which the high cost of primate research does not allow for large-scale experimentation (i.e., when large numbers of oocytes and embryos are needed), ruminants would be an ideal solution. Represented by the cow and sheep, domestic ruminants feature a fertilization strategy similar to that of the human. In addition, large numbers of gametes can be obtained wherever farms and slaughterhouses are accessible. Moreover, the detailed information on ruminant fertilization is strengthened by years of research and well-defined reproductive technology aimed at increasing the productivity of farm animals. Ruminants and rhesus monkeys have been extensively studied, and the data from these studies have been extrapolated in order to propose new strategies for the diagnosis and treatment of human infertility.