Adverse Outcomes of Assisted Reproductive Technologies: Genetics or Epigenetics?

辅助生殖技术的不良后果：遗传学还是表观遗传学？

• 批准号: 8735977
• 负责人: Margareta Pisarska
• 金额: $ 65.06万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735977
• 关键词: Abruptio Placentae; Address; Adverse event; Affect; Age; Animals; Apoptosis; Assisted Reproductive Technology; Bioethics; Biological Markers; Blood Pressure; Cataloging; Catalogs; Cell Line; Cells; Child; Chorionic Villi Sampling; Chromosome Mapping; Clinical; Congenital Abnormality; Congresses; Copy Number Polymorphism; Coupled; Couples; DNA Methylation; Data; Databases; Defect; Development; Disease; Embryo; Ensure; Environment; Epigenetic Process; Exposure to; Fertilization; Fertilization in Vitro; Fetal Development; First Pregnancy Trimester; Gene Expression; Gene Expression Profiling; Gene Targeting; General Population; Genes; Genetic; Genetic Predisposition to Disease; Goals; Health; Human; In Vitro; Individual; Infertility; Laboratories; Lead; Link; Low Birth Weight Infant; Methylation; Modality; Modification; Molecular; Molecular Profiling; National Institute of Child Health and Human Development; Nucleotides; Patients; Perinatal mortality demographics; Placenta; Placentation; Population; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Premature Birth; Premature Labor; Procedures; Process; RNA; Risk; Role; Sampling; Small for Gestational Age Infant; Statistical Methods; Structural Congenital Anomalies; Technology; Testing; Time; Tissues; Transcript; Variant; Weight Gain; adverse outcome; base; biobank; cell motility; density; exome; fasting glucose; fetal; genome-wide; imprint; in vivo; innovation; novel; prenatal; public health relevance; reproductive; trophoblast

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.

描述（由申请人提供）：不育会影响美国约610万人，相当于生殖年龄人口的10％。结果，使用辅助生殖技术（ART），包括体外受精（IVF），已经显着增长，因此使用IVF的美国出生的婴儿中有将近1％的婴儿被构想。这些妊娠的不良后果风险增加，包括低出生体重，先兆子痫，胎盘，胎盘，胎盘previa，早产和围产期死亡率，其中许多可能归因于胎盘异常和滋养层分化的异常。 并且还增加了重大结构性先天缺陷，烙印疾病以及可能额外的长期健康后果的风险。这项研究的目的是确定可能导致这些风险增加的分子机制，以及这些机制是由于使用ART还是来自潜在的不育症。通过我们的产前生物座席，我们可以独特地进入绒毛膜绒毛采样（CVS）中剩余的废弃组织。值得注意的是，这些样品与妊娠相关数据和妊娠结局的数据库耦合，并且可以从相同的怀孕中获得期限胎盘样本，因为在Cedars-Sinai提供了多达45％的CVS患者。这使我们能够检查在胎盘发生的时期获得的妊娠滋养细胞，在正在进行的怀孕期间，可以遵循到期限及以后。我们的初步数据显示，通过IVF，b）在体内怀孕的妊娠以及C）妊娠自发地怀孕的CVS滋养细胞的基因表达谱之间的显着差异。在此应用中，我们将使用全基因组遗传，表观遗传学和基因表达分析来区分不育遗传学和IVF诱导的表观遗传学的影响 胎盘功能和最终胎儿发育的变化。具体而言，我们提议量化和比较基因组DNA甲基化，以及全基因组的SNP以及拷贝数变化（CNV）谱（CNV）和外显元的非同义SNP特征，来自于怀孕的CVS样本，伴有不育和体外的体内生育于体内的怀孕。为了区分宫内环境的作用，我们还将量化和比较与同一妊娠子集中术语胎盘样品中基因表达和CpG DNA甲基化。最后，我们将使用原发性滋养细胞培养物和滋养细胞细胞系确定基因的功能活性，并发现其在滋养细胞细胞迁移，入侵和细胞凋亡中的作用，这可能导致异常的胎盘。这种真正综合和创新的方法将使我们能够阐明有助于妊娠相关并发症和不良后果的分子机制，并确定在使用ART构想的妊娠中是否改变了这些机制或与潜在的不育相关。