Metformin Effects Placental Trophoblast Function

二甲双胍影响胎盘滋养层功能

• 批准号: 10608822
• 负责人: Amy Miyoshi Valent
• 金额: $ 19.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608822
• 关键词: Admission activity; Adverse effects; Affect; Area; Birth Weight; Blood Glucose; Cell Differentiation process; Cell Proliferation; Cells; Chemicals; Child; Childhood; Clinical Trials; Communication; DNA; DNA Methylation; Data; Diabetes Mellitus; Dose; Drug Exposure; Epigenetic Process; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; Fetal Development; Fetal Growth; Fetus; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Gestational Age; Gestational Diabetes; Growth; Growth and Development function; Health; Homeostasis; Hormones; Human Chorionic Gonadotropin; Image; In Vitro; Inflammation; Insulin; Intervention; Knowledge; Life Style Modification; Metabolic; Metabolism; Metformin; Methylation; Mitochondria; Morbidity - disease rate; Morphology; Neonatal; Neonatal Intensive Care Units; Neonatal Mortality; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Obesity; Oral; Outcome; Pathway interactions; Perinatal; Pharmaceutical Preparations; Placenta; Placental Hormones; Plasma; Polycystic Ovary Syndrome; Population; Pregnancy; Pregnancy Complications; Production; Publishing; Reporting; Respiration; Risk; Role; Safety; Small for Gestational Age Infant; Syncytiotrophoblast; Testing; Time; United States; Visual; Weight; adverse outcome; blood lipid; body system; cardiometabolism; cell type; comorbidity; cytotrophoblast; epigenomics; fetal; fetal programming; gene function; gestational weight gain; insight; mRNA Expression; neonatal morbidity; offspring; organ growth; peptide hormone; perinatal outcomes; pharmacologic; prenatal exposure; protein expression; transcriptomics; trophoblast

PROJECT SUMMARY Optimal fetal growth and development requires robust placental function, which is affected by blood glucose and lipid concentrations but also potentially chemical/drug exposures. Drugs may alter epigenetic homeostasis by direct or indirect mechanisms (transcription activity) that can persist long after exposure to the drug (i.e. pharmacoepigenomics). Our preliminary data has shown differentially methylated regions in DNA from trophoblasts in pregnancies complicated by gestational diabetes (GDM) compared to non-GDM trophoblasts. Moreover, metformin and GDM independently and significantly decreases mitochondrial respiration and placental hormone gene and protein expression in placental trophoblasts. Placental hormones, particularly β- hCG are necessary for normal fetal growth and development. Recent trials using metformin in pregnancy has demonstrated potential maternal benefits such as lower gestational weight gain but higher rates of small-for- gestational age infants and greater weight z-scores and adiposity in children. This highlights the critical gap in our knowledge of the effects of metformin on placental health and its role on potential beneficial and adverse perinatal outcomes. Our objectives are to (Aim 1) determine the effects of metformin on trophoblast epigenomic and transcriptomic profiles and (Aim 2) determine the degree to which metformin treatment suppresses cytotrophoblast maturation and hCG production in GDM and non-GDM placentas. Epigenomic and transcriptomic profiles from isolated trophoblasts in culture for 8-hrs (cytotrophoblasts) and 72-hrs (syncytiotrophoblasts) exposed to metformin will be compared to unexposed trophoblasts from GDM and non- GDM pregnancies. Live cell, time-lapsed imaging throughout trophoblast maturation (8, 24, 48, 72-hrs in vitro culture) will be done to visually correlate morphological maturation with gene markers of trophoblast differentiation and β-hCG production in the presence or absence of metformin cell exposure. Metformin and GDM must be studied together and concurrently because published trial data (i.e. obesity and polycystic ovarian syndrome) has shown they are independently associated with the growth and health of the fetus. We acknowledge metformin has been studied in many organ systems but how it effects the placenta and specifically the trophoblast cells is poorly understood. We believe that it is important to understand the degree to which metformin affects the maturation and metabolism of placental trophoblasts and whether epigenetic mechanisms underlie changes in gene expression patterns that regulate trophoblast function in GDM and non-GDM placentas. This study will offer new information that may caution the use of metformin in pregnancy and set the stage for more refined clinical trials.

项目概要 胎儿的最佳生长和发育需要强大的胎盘功能，而胎盘功能受到血糖和 脂质浓度以及潜在的化学/药物暴露可能会改变表观遗传稳态。 直接或间接机制（转录活性）在接触药物后可以持续很长时间（即。 药物表观基因组学）。我们的初步数据显示 DNA 中存在差异甲基化区域。 妊娠期并发妊娠糖尿病 (GDM) 的滋养层细胞与非 GDM 滋养层细胞相比。 此外，二甲双胍和 GDM 独立且显着降低线粒体呼吸和 胎盘滋养细胞中胎盘激素基因和蛋白的表达，特别是 β-胎盘激素。 hCG 对于胎儿的正常生长和发育是必需的，最近在妊娠期间使用二甲双胍的试验表明。 潜在的孕产妇益处，例如已证实妊娠期体重增加较低，但小儿妊娠率较高 孕龄婴儿和儿童体重 z 分数较高，这凸显了儿童肥胖的关键差距。 我们对二甲双胍对胎盘健康的影响及其潜在有益和不利作用的了解 我们的目标是（目标 1）确定二甲双胍对滋养层表观基因组的影响。 和转录组图谱以及（目标 2）确定二甲双胍治疗抑制的程度 GDM 和非 GDM 胎盘中细胞滋养层的成熟和 hCG 的产生。 培养 8 小时（细胞滋养层）和 72 小时的分离滋养层细胞的转录组谱 暴露于二甲双胍的（合体滋养层）将与 GDM 和非妊娠期未暴露的滋养层进行比较。 GDM 妊娠的滋养层成熟过程中的活细胞延时成像（体外 8、24、48、72 小时） 培养）将在视觉上将形态成熟与滋养层的基因标记相关联 在存在或不存在二甲双胍和二甲双胍的情况下细胞分化和 β-hCG 产生。 GDM 必须同时进行研究，因为已发表的试验数据（即肥胖和多囊卵巢） 综合征）已表明它们与胎儿的生长和健康独立相关。 承认二甲双胍已在许多器官系统中进行了研究，但它如何影响胎盘，特别是 我们对滋养层细胞知之甚少，但了解其程度非常重要。 二甲双胍影响胎盘滋养细胞的成熟和代谢及其表观遗传机制 GDM 和非 GDM 中调节滋养层功能的基因表达模式发生变化 这项研究将提供新的信息，可能会警告妊娠期间使用二甲双胍并确定 更精细的临床试验阶段。