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: 9067824
• 负责人: Margareta Pisarska
• 金额: $ 79.34万
• 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 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067824
• 关键词: Abnormal placentation; Abruptio Placentae; Address; Adverse event; Affect; Animals; Apoptosis; Assisted Reproductive Technology; Bioethics; Blood Pressure; Catalogs; Cell Line; Cells; Child; Chorion; 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; Modernization; Modification; Molecular; Molecular Profiling; National Institute of Child Health and Human Development; Nucleotides; Patients; Perinatal mortality demographics; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Premature Labor; Procedures; Process; RNA; Risk; Role; Sampling; Small for Gestational Age Infant; Statistical Methods; Structural Congenital Anomalies; Technology; Testing; Therapeutic; Time; Tissues; Transcript; Variant; Villus; Weight Gain; adverse outcome; aging population; biobank; biomarker development; cell motility; density; exome; fasting glucose; fetal; genetic profiling; genetic technology; genome-wide; imprint; in vivo; infertility treatment; innovation; novel; placenta previa; prenatal; public health relevance; reproductive; transcriptome sequencing; 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）：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) 的使用急剧增加，以至于美国近 1% 的婴儿是通过 IVF 受孕的。这些妊娠出现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、早产和围产儿死亡率，其中许多可能归因于妊娠前三个月的胎盘和滋养层分化异常。 并且还增加了重大结构性出生缺陷、印记障碍以及可能产生其他长期健康后果的风险。本研究的目的是确定可能导致这些风险增加的分子机制，以及这些风险是否是由使用 ART 引起的，还是由潜在的不孕症引起的。通过我们的产前生物样本库，我们可以独特地获取绒毛膜绒毛取样 (CVS) 中剩余的废弃组织。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，并且足月胎盘样本可来自同一妊娠，因为多达 45% 的 CVS 患者在 Cedars-Sinai 分娩。这使我们能够检查在胎盘发生期间、持续妊娠期间获得的妊娠早期滋养层细胞，该妊娠可以持续到足月及以后。我们的初步数据显示，a) 通过 IVF 受孕的妊娠，b) 体内受孕的不孕相关妊娠，以及 c) 自然受孕的 CVS 滋养层细胞的基因表达谱之间存在显着差异。在此应用中，我们将使用全基因组遗传学、表观遗传学和基因表达谱来区分不孕症遗传学和 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。具体来说，我们建议量化和比较来自不孕不育妊娠和体外与体内受精妊娠的 CVS 样本中的基因表达和 CpG DNA 甲基化，以及全基因组 SNP 和拷贝数变异 (CNV) 谱以及全外显子组非同义 SNP 谱，与自然妊娠相比。为了区分宫内环境的影响，我们还将量化和比较同一妊娠子集的足月胎盘样本中的基因表达和 CpG DNA 甲基化。最后，我们将使用原代滋养层培养物和滋养层细胞系来鉴定表达发生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，这可能导致异常胎盘。这种真正综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后果的分子机制，并确定这些机制是否在使用 ART 受孕的妊娠中发生改变或与潜在的不孕症相关。