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).

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD068157-03
Application #
8446931
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$477,397
Indirect Cost
$121,757
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hur, Stella K; Freschi, Andrea; Ideraabdullah, Folami et al. (2016) Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver-Russell syndrome phenotypes. Proc Natl Acad Sci U S A 113:10938-43
Meyer-Ficca, Mirella L; Ihara, Motomasa; Bader, Jessica J et al. (2015) Spermatid head elongation with normal nuclear shaping requires ADP-ribosyltransferase PARP11 (ARTD11) in mice. Biol Reprod 92:80
Bryant, Jessica M; Donahue, Greg; Wang, Xiaoshi et al. (2015) Characterization of BRD4 during mammalian postmeiotic sperm development. Mol Cell Biol 35:1433-48
Hu, Jialei; Donahue, Greg; Dorsey, Jean et al. (2015) H4K44 Acetylation Facilitates Chromatin Accessibility during Meiosis. Cell Rep 13:1772-80
Butts, Samantha F; Guidotti, Tee L (2014) What are some potential reproductive hazards in the hospital environment? J Occup Environ Med 56:e163-5
Ihara, Motomasa; Meyer-Ficca, Mirella L; Leu, N Adrian et al. (2014) Paternal poly (ADP-ribose) metabolism modulates retention of inheritable sperm histones and early embryonic gene expression. PLoS Genet 10:e1004317
Mainigi, Monica A; Olalere, Devvora; Burd, Irina et al. (2014) Peri-implantation hormonal milieu: elucidating mechanisms of abnormal placentation and fetal growth. Biol Reprod 90:26
Butts, Samantha F; Owen, Carter; Mainigi, Monica et al. (2014) Assisted hatching and intracytoplasmic sperm injection are not associated with improved outcomes in assisted reproduction cycles for diminished ovarian reserve: an analysis of cycles in the United States from 2004 to 2011. Fertil Steril 102:1041-1047.e1
Butts, Samantha F; Ratcliffe, Sarah; Dokras, Anuja et al. (2013) Diagnosis and treatment of diminished ovarian reserve in assisted reproductive technology cycles of women up to age 40 years: the role of insurance mandates. Fertil Steril 99:382-8
Butts, Samantha F; Guo, Wensheng; Cary, Mark S et al. (2013) Predicting the decline in human chorionic gonadotropin in a resolving pregnancy of unknown location. Obstet Gynecol 122:337-43

Showing the most recent 10 out of 17 publications