Adverse Outcomes of Assisted Reproductive Technologies: Genetics or Epigenetics?

描述（由申请人提供）：不孕症影响了美国约610万人，相当于育龄人口的10%。因此，包括体外受精（IVF）在内的辅助生殖技术（ART）的使用急剧增加，因此在美国出生的婴儿中有近1%是通过体外受精受孕的。这些妊娠发生不良后果的风险增加，包括低出生体重、先兆子痫、胎盘早剥、前置胎盘、早产和围产期死亡，其中许多可能归因于妊娠早期胎盘和滋养细胞分化异常。

DESCRIPTION (provided by applicant): Infertility affects about 6.1 million people in the U.S., equivalent to 10% of the reproductive age population. As a result, the use of assisted reproductive technologies (ART), including in vitro fertilization (IVF) has risen dramatically, so that nearly 1% of babies born in the US are conceived using IVF. These pregnancies are at increased risk of adverse outcomes, including low birth weight, preeclampsia, placental abruption, placenta previa, preterm delivery, and perinatal mortality, many of which may be attributed to abnormalities of placentation and trophoblast differentiation in the first trimester, and also have increased risks for major structural birth defects, imprinting disorders and possibly additional long term health consequences. The goal of this study is to determine the molecular mechanisms which may contribute to these increased risks, and whether these result from the use of ART, or from the underlying infertility. Through our Prenatal Biorepository, we have unique access to discarded tissue remaining from chorionic villus sampling (CVS). Significantly, these samples are coupled to a database of pregnancy-related data and pregnancy outcomes, and term placental samples are available from the same pregnancies, as up to 45% of CVS patients deliver at Cedars-Sinai. This enables us to examine first trimester trophoblasts obtained during the period in which placentation occurs, in ongoing pregnancies which can be followed to term and beyond. Our preliminary data show significant differences between gene expression profiles of CVS trophoblast cells in a) pregnancies conceived via IVF, b) infertility-associated pregnancies conceived in vivo, and c) pregnancies conceived spontaneously. In this application, we will use genome-wide genetic, epigenetic, and gene expression profiling to differentiate the impact of infertility genetics and IVF-induced epigenetic changes on placental function and ultimately fetal development. Specifically, we propose to quantify and compare gene expression and CpG DNA methylation, as well as genome-wide SNP and copy number variation (CNV) profiles and exome-wide non-synonymous SNP profiles, in CVS samples from pregnancies conceived with infertility and in vitro versus in vivo fertilization, as compared to spontaneous pregnancies. To distinguish the effects of intrauterine environment, we will also quantify and compare gene expression and CpG DNA methylation in term placental samples from a subset of the same pregnancies. Lastly, we will identify the functional activity of genes whose expression is found to be altered, using primary trophoblast cultures and trophoblast cell lines, and evaluate their roles in trophoblast cell migration, invasin and apoptosis, which may lead to aberrant placentation. This truly integrated and innovative approach will allow us to elucidate the molecular mechanisms that contribute to pregnancy-related complications and adverse outcomes, and to determine whether these are altered in pregnancies conceived using ART or related to the underlying infertility.