Oocyte and Preimplantation Embryo Perturbations: Long-Term Effects on Offspring

Kelle H. Moley, M.D.

Over the last two decades epidemiological and clinical observations have lead to the hypothesis that the risk of developing some chronic diseases in adulthood is influenced not only by genetic and adult lifestyle factors, but also by maternal physiologic and environmental factors acting in early fetal life. This phenomenon has been termed “Fetal Origins of Adult Disease.” More recent work in animal models suggests that even the oocyte, early zygote, cleavage stage embryo and blastocyst stage embryo are sensitive to changes in the maternal milieu that may cause lasting effect in offspring. This set of reviews attempts to establish the “Embryonic Origins of Adult Disease” as an alternative mechanism. There are no published, long-term followup studies in humans examining whether environmental exposure during the same period of development has any long lasting effects on children, especially those born following in vitro fertilization (IVF). Reports have demonstrated, however, that domestic animal embryo culture is associated with a higher risk of overgrowth (large offspring syndrome) associated with changes in imprinting. Several studies have reported an association between assisted reproductive technologies (ART) and imprinting disorders in children conceived by these technologies, however, the cause of these disorders and the mechanisms responsible are still speculative. The first two reviews in this issue address these findings. Lawrence and Moley present the background of epigenetics and germ cell development and discuss the human imprinting syndromes in general as well as those linked to human ART by small clinical observational studies. Sinclair, in the second review discusses ART and potential contribution of different factors to poor perinatal outcomes in humans and animals.

One question that arises in a discussion of developmental plasticity is whether the inciting event leading to long term programming of the offspring occurs during oocyte development and maturation or during preimplantation development of the cleavage stage embryo to blastocyst stage. In vitro maturation is defined as the completion of meiosis of the denuded oocyte in a culture dish, without the contribution of the somatic granulosa cells and outside of the original follicle. Although this technique has been used extensively as a research tool to investigate the process of maturation and has been used in domestic animal ART, the area of human clinical IVM is still evolving. Human oocyte IVM culture conditions are far from optimal. Implantation rates are very poor, however, a bigger concern is the potential for these early perturbation to have long lasting health effects on the offspring. Similar poor outcomes have been demonstrated with mouse and bovine IVM. In this issue, Banwell and Thompson address the issue surrounding IVM in mammals and the potential consequences of it use in the future on pregnancy outcome and offspring health. On the other hand abnormal programming in ART may be the consequence of perturbations to the preimplantation embryo stage, since much work has demonstrated sensitivity of cleavage and blastocyst stage embryos to in vivo and in vitro manipulations. Environment changes during this period have been shown to affect a large number of epigenetic, cellular and metabolic processes in the embryos and some have been linked with abnormal postnatal phenotypes. Watkins et al review their elegant findings on alterations in maternal protein diet during the preimplantation period and outcomes in offspring physiology. Their work is instrumental in understanding the potential mechanisms and targets. Having this information, protocols in ART and embryo culture may be optimized to improve fetal outcomes and perhaps long-term offspring health.

These observations, however, have much more far reaching implications, as the last three reviews point out. Although improvements in the rates of miscarriages and malformations in women with type 1 and type 2 diabetes have been demonstrated with the improvement in glycemic control over the past 50 years, these women still have a 3- to 5-fold higher incidence of poor pregnancy outcomes. Data presented by Jungheim and Moley suggest that exposure of the oocyte and/or preimplantation embryo to the maternal milieu predisposed these resulting gametes and zygotes to poor competence and permanently programs them develop metabolic abnormalities, poor fetal growth patterns as well as malformations. By decreasing preimplantation embryo expression of glucose transporter, GLUT1, during the periimplantation period, many of the abnormalities associated with maternal diabetes are recapitulated suggesting that nutrient deprivation, glucose specifically, has long lasting effects on offspring health. Polycystic ovary syndrome (PCOS) is another maternal metabolic condition that also has long lasting effects on oocytes possibly through permanent changes to the oocyte occurring during aberrant folliculogenesis. Patel and Carr review the data supporting oocyte origins of poor pregnancy outcome in PCOS patients. The follicular environment is exposed to the hyperandrogenism, hyperinsulinemia and hyperlipidemia of PCOS woman, which undoubtedly adversely affects the resulting oocyte before and during maturation. This review presents a clinical scenario, representing perhaps the only one in which the benefits of IVM may outweigh the risks. Smoking and poor ovarian function have long been linked by the clinical association between premature ovarian failure and tobacco use. In the last article, Cooper and Moley review the most recent studies examining the association between oocyte quality in ART and smoking. Potential mechanisms to explain these findings are present and therapeutic options discussed.

In conclusion, this collection of reviews attempts to present the most recent evidence to support development origins of poor pregnancy outcomes from the earliest stages of gametogenesis and embryogenesis. Evidence for epigenetic, cellular, and metabolic mechanisms are presented that may alter the pattern of cell division and differentiation, gene expression and finally infant and adult phenotype.