Perinatal and long-term outcomes of infants conceived with the assistance of in-vitro fertilization (IVF) has become a major focus of the Reproductive Sciences Branch of NICHD. Epidemiological studies have indicated that even singleton pregnancies are at increased risk for a number of adverse perinatal outcomes, including low birth weight and preterm delivery. In addition, genetic syndromes (i.e Beckwith-Widemann, Angelman) and some tumors (i.e retinoblastoma) which are frequently associated with epigenetic dysregulation have also been associated with assisted reproductive technologies. Published reports from our own and other laboratories, along with our preliminary observations, show that following hormonal stimulation along with the in vitro manipulation of human gametes and/or embryos, extra-embryonic and fetal tissues exhibit particular susceptibility to both methylation and specific gene expression differences. Because oxygen appears to play a central role in human trophoblast differentiation the Pi's laboratory along with his collaborators now have the unique opportunity to study the effects of this critical pre-implantation exposure on embryonic and extra-embryonic tissues taking advantage of an RMN clinical trial comparing livebirth results following culture of early human embryos in a physiologic (5%) vs. a 20% oxygen atmosphere. In the first specific aim, methylation patterns and gene expression profiles will be evaluated in placenta and cord blood following delivery of babies conceived in vitro and cultured at 5% vs. 20% oxygen tension and compare them to in vivo conceived controls. In addition, the correlation of markers of early pregnancy trophoblast function with methylation differences and gene expression profiles of placenta at birth will be determined. In the second specific aim, the correlation between trophoblast differentiation (morphologic, hormonal and functional), methylation patterns and regulatory gene expression utilizing our in vitro model of human trophoblast differentiation exposed to different oxygen concentrations in vitro. Results from this discovery driven proposal will set the stage for subsequent mechanistic studies and should provide information for the direction of experiments to be performed in the mouse model (see project II).
The correlation of clinical data with specific methylation and gene expression differences will generate invaluable information for the initiation of follow-up basic studies on the roles of specific genes and epigenetic regulatory processes involved in placental development, processes critical to explain and possibly prevent/treat adverse clinical phenotype(s) such as low birth weight and preterm delivery.
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