Why Primate Models Are Critical to Understanding Human Development and Subfertility

A number of reasons can be used to rationalize the NHP as a relevant model of humans for both anatomic and pathophysiological aspects of their respective biology. A menstrual cycle is shared among macaques and women; rodents have an estrous cycle indicating differing endocrine controls on the reproductive systems in these species. There is also approximately 95% genetic identity between humans and macaques [18] while significantly less homology exists between mouse and human genomes [19, 20]. For meaningful studies aimed at resolving the pathophysiology of embryo loss and infertility in humans, a relevant animal model must be used that reflects the basic physiology and morphology of human fertilization and embryo development.

Current knowledge of fundamental aspects of mammalian embryology has been derived primarily from studies in the mouse [21].

However, generalizations from rodents to humans are less than accurate owing to significant differences in the two biological systems. Rodent models often fail to exhibit therapeutic meaning when physiologic-based interventions are attempted. The mouse, for example, typically exhibits less than 1% pre-implantation embryonic aneuploidy rates making it difficult or impossible to derive information regarding origins of human aneuploidy from the mouse [22]. In addition, the murine model is not adequate for these studies for two very significant reasons: (1) the transition from maternal to embryonic transcription occurs at the one- to two-cell stage in the mouse unlike the 6-8 cell stage in primates, including humans, and (2) unlike that of the rhesus monkey and human, the mouse oocyte does not require a male centriole to initiate cleavage [23-25]. The latter difference is critically important and is exemplified by the failure of development of a mouse model prior to widespread clinical introduction of intracytoplasmic sperm injection (ICSI) into the in vitro fertilization (IVF) clinic [3].

In the United States, between 1 and 1.5 million human embryos are produced annually for clinical IVF programs. These embryos have variable and poorly defined potential for successful implantation and development, in large part due to meiotic and mitotic errors [26-28]. Thus, only approximately 6% of all embryos lead to live births [26-28]. Further, transfer of multiple embryos with variable and unknown developmental potential is paradoxically associated with both high rates of embryo loss and increased incidence of multiple births [29]. It is, however, unlikely that IVF success rates will improve with little ability to predict embryo developmental potential and to select embryos for transfer accordingly. Moreover, it is thought that the incidence of human embryonic aneuploidy observed in vitro might be similar to in vivo given that only about 30% of human conceptions result in live births and chromosomal abnormalities have been reported in more than 70% of spontaneous miscarriages [30-36]. Recent studies [37, 38] confirmed that the incidence of aneuploidy in human embryos is approximately 70% and that the most common errors are mitotic in origin [37]. Furthermore, euploid embryos followed precise timing of first cytokinesis and cell cycle lengths of the first two cleavage divisions [38]. Generation of human embryonic aneuploidy is complex with contribution from chromosome-containing fragments/micronuclei that frequently emerge and may persist or become reabsorbed during interphase.

These results suggest that cell cycle and fragmentation of individual blastomeres are diagnostic of ploidy and likely of clinical relevance in reducing transfer of embryos prone to miscarriage [31, 34, 37, 39-41]. As discussed next, early developmental checkpoints can be closely modeled in the macaque model that may shed light on pathophysiology of meiosis and mitosis in human embryos.

 
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