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: 8529827
• 负责人: Margareta Pisarska
• 金额: $ 61.9万
• 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/8529827
• 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; 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(申请人提供)：美国约有610万人患有不孕症，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)的使用大幅增加，因此在美国出生的婴儿中有近1%是通过试管受精受孕的。这些妊娠的不良结局的风险增加，包括低出生体重、先兆子痫、胎盘早剥、前置胎盘、早产和围产儿死亡，其中许多可能归因于妊娠早期胎盘和滋养细胞分化的异常， 而且还增加了重大结构性出生缺陷、印记障碍的风险，并可能带来额外的长期健康后果。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，以及这些风险是由ART的使用还是潜在的不孕症造成的。通过我们的产前生物库，我们拥有独特的途径来获取绒毛样本(CVS)中残留的废弃组织。值得注意的是，这些样本与妊娠相关数据和妊娠结局的数据库相结合，并且可以从相同的妊娠获得足月胎盘样本，因为多达45%的CVS患者在锡达斯-西奈分娩。这使我们能够检查在胎盘形成发生期间获得的早期妊娠滋养层细胞，在持续怀孕期间可以跟踪到足月或以后。我们的初步数据显示，CVS滋养层细胞的基因表达谱在a)通过体外受精受孕、b)体内受孕的不孕相关妊娠和c)自然受孕的妊娠之间存在显著差异。在这项应用中，我们将使用全基因组遗传、表观遗传学和基因表达谱来区分不孕症遗传学和体外受精诱导表观遗传学的影响。 胎盘功能的变化，最终影响胎儿发育。具体地说，我们建议量化和比较CVS样本中的基因表达和CpG DNA甲基化，以及基因组范围的SNP和拷贝数变异(CNV)谱以及外显子范围的非同义SNP谱，与自然妊娠相比，体外受精和体内受精的CVS样本。为了区分宫内环境的影响，我们还将量化和比较相同妊娠的子集足月胎盘样本中的基因表达和CpG DNA甲基化。最后，我们将利用原代滋养层细胞培养和滋养层细胞系来鉴定表达改变的基因的功能活性，并评估它们在滋养层细胞迁移、侵袭和凋亡中的作用，这些可能导致异常的胎盘形成。这种真正整合和创新的方法将使我们能够阐明导致妊娠相关并发症和不良结果的分子机制，并确定这些因素在使用ART受孕的怀孕中是否发生了变化，或者与潜在的不孕症有关。