Trophoblast Differentiation in In Vivo and In Vitro Fertilized Embryos

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Infertility, a medical problem of widespread proportions, affects one in seven couples. Fortunately, treatment options are available, of which the most successful include assisted reproductive technologies (ART) such as in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI). These procedures require gametes to be fertilized in vitro and the resulting embryos to be cultured for 3 to 5 days before transfer to the uterus. Such interventions are very successful, providing excellent pregnancy rates. However, new evidence suggests that these procedures are not totally benign. Human studies show an increased incidence of maternal complications, such as preeclampsia, gestational diabetes and preterm labor in women who conceive by ART. Increased fetal complications, including low and very-low birth weights, imprinting disorders and congenital malformations, are also observed. Compelling animal data reveal that offspring produced by ART exhibit abnormal behavior, abnormal imprinting and embryonic gene expression as well as abnormal phenotypes, such as the large offspring syndrome in cattle. Undoubtedly, multiple mechanisms lead to these conditions and their causes are largely unknown. Most likely, they include altered gene expression and abnormal imprinting, which lead to changes in the structure and function of tissues, organs, and systems. The Fetal Onset of Adult Disease (FOAD) hypothesis holds that the embryo and fetus are more sensitive than the adult to environmental insults, which can result in structural malformations or functional changes that lead, in later life, to chronic diseases. Our preliminary data show that mouse embryos produced by IVF have a reduced number of trophoblast cells. Accordingly, we propose two specific aims to test the hypothesis that IVF compromises important aspects of embryonic and placental development. The goal of Aim 1 is to compare the gene expression patterns [inner cell mass (ICM) and trophoblast (TB)] and differentiative potential of embryos that are generated in vivo and in vitro. The goal of Aim 2 is to obtain functional correlates of the observed differences by assessing the effects of IVF on implantation. Thus, at the conclusion of these experiments, we shall have advanced our current understanding of the detrimental effects of in vitro development on the embryo, information that is crucial to designing culture conditions that better replicate the in vivo environment.