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.

项目总结 最佳的胎儿生长和发育需要强大的胎盘功能，而胎盘功能受血糖和 脂类浓度，但也潜在的化学/药物暴露。药物可能通过以下方式改变表观遗传动态平衡 直接或间接机制(转录活性)，可在长期接触药物后持续存在(即 药物表观基因组学)。我们的初步数据显示，DNA中的甲基化区域与 妊娠合并妊娠期糖尿病(GDM)的滋养细胞与非GDM滋养细胞的比较。 此外，二甲双胍和GDM单独显著降低线粒体呼吸和 胎盘滋养层细胞胎盘激素基因和蛋白的表达。胎盘激素，特别是β- 人绒毛膜促性腺激素是胎儿正常生长发育所必需的。最近在怀孕期间使用二甲双胍的试验已经 显示了潜在的产妇益处，如较低的妊娠体重增加，但较高的小儿率 胎龄、婴儿和较大的体重、Z分数和儿童肥胖。这突显了 我们对二甲双胍对胎盘健康的影响及其对潜在有利和不利因素的作用的认识 围产儿结局。我们的目标是(目标1)确定二甲双胍对滋养细胞表观基因组的影响 和转录谱和(目标2)确定二甲双胍治疗抑制的程度 妊娠期糖尿病和非妊娠期糖尿病胎盘细胞滋养层细胞成熟和hCG的产生表观基因组学和 分离的滋养层细胞培养8小时和72小时的转录图谱 (合体滋养层细胞)暴露于二甲双胍将与GDM和非GDM未暴露的滋养层细胞进行比较 妊娠期糖尿病。活细胞，滋养层成熟过程中的时间推移成像(体外8，24，48，72小时 培养)将在视觉上将形态成熟与滋养层细胞的基因标记相关联 在有或没有二甲双胍细胞暴露的情况下，分化和β-hCG的产生。二甲双胍和 妊娠期糖尿病必须同时进行研究，因为已公布的试验数据(即肥胖和多囊卵巢 已表明它们与胎儿的生长和健康是独立相关的。我们 众所周知，二甲双胍在许多器官系统中都有研究，但它是如何影响胎盘的，特别是 人们对滋养层细胞知之甚少。我们认为，重要的是要了解 二甲双胍对胎盘滋养层细胞成熟代谢及表观遗传机制的影响 妊娠期糖尿病和非妊娠期糖尿病滋养细胞功能调控基因表达模式的变化 胎盘。这项研究将提供新的信息，可能会警告怀孕期间二甲双胍的使用，并设置 为更精细的临床试验做准备。