Placental adaptive mechanisms to environmental exposures.

胎盘对环境暴露的适应机制。

• 批准号: 9762925
• 负责人: Almudena Veiga-Lopez
• 金额: $ 34.48万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762925
• 关键词: Address; Adult; Adverse effects; Affect; Affinity; Animal Model; Asthma; Blood Circulation; Canada; Cardiovascular Diseases; Catheterization; Cell Adhesion Molecules; Cell Line; Cell-Cell Adhesion; Cells; Chemicals; Chronic Disease; Clinical; Communication; Communities; Data; Defect; Development; Disease; Doppler Ultrasound; Dose; Down-Regulation; E-Cadherin; EGF gene; Endocrine; Endocrine Disruptors; Endocrine system; Environment; Environmental Exposure; Environmental Pollutants; Equilibrium; Exposure to; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Gene Expression; Genes; Glycoproteins; Health; Human; Human Cell Line; Human Chorionic Gonadotropin; Impairment; In Vitro; Incidence; Industrialization; Inflammation; Insulin; Left ventricular structure; Long-Term Effects; Malignant Neoplasms; Measures; Mediating; Membrane; Metabolic Diseases; Molecular; Monitor; Morphology; Mothers; Mutation; Neuroglia; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Outcome; Oxygen; Pathway interactions; Personal Satisfaction; Phenotype; Placenta; Policies; Pregnancy; Preventive measure; Production; Progesterone; Progesterone Receptors; Proteins; Public Health; Regulation; Risk; Safety; Sheep; Small Interfering RNA; Source; Steroids; Teratogenic effects; Testing; Time; Tissues; Transcript; Up-Regulation; Weight; Work; adipocyte differentiation; autism spectrum disorder; bisphenol A; cardiometabolism; chemical substitution; consumer product; cytotrophoblast; epidemiology study; exposed human population; fetal; genetic manipulation; genome wide association study; improved; in utero; in vivo; in vivo Model; in vivo monitoring; insight; interdisciplinary approach; longitudinal design; male; manufacturing process; mother nutrition; novel; offspring; prenatal exposure; protein expression; receptor expression; reproductive; safety testing; sex; tool; transcription factor; trophoblast; virtual

ABSTRACT The placenta is the gateway between the mother and the developing fetus. Placental dysfunction can impair fetal growth and induce long-term effects in the progeny, including increased risk for metabolic diseases. The delicate balance of feto-maternal communication / exchange can be affected by a number of factors including maternal diet and diseases and / or exposure to endocrine disrupting compounds (EDCs). EDCs are synthetic or natural chemicals that interfere with the normal function of the endocrine system with some EDCs having steroidal activity. Fetal exposure to such EDCs can pose a threat to adult well-being. Current policy regulations are limiting the use of one of such EDCs, bisphenol A (BPA), in the manufacture process of consumer products. Emergence of new, untested, industrial chemical substitutes such as bisphenol S (BPS), an EDC with very distinct steroid affinities compared to BPA, are on the rise. Understanding the health risks posed by emerging EDC exposures is critical. Our preliminary studies using sheep as an in vivo model and in vitro studies using human cytotrophoblasts demonstrate that BPS exposure alters placental trophoblast function. BPA does not lead to a similar placental phenotype, highlighting critical and unexplored differences among bisphenolic EDCs. Our preliminary data suggest that BPS mediates its action via the progesterone receptor pathway. In our animal model, gestational BPS exposure also impacts fetal size and leads to cardio-metabolic disruptions. Studies described in this proposal will capitalize on a unique animal model of feto-maternal communication, primary trophoblast cells and trophoblast cell lines to test a novel hypothesis for the developmental origin of cardio-metabolic disorders with specific emphasis on understanding the molecular mechanisms whereby BPS compromises trophoblast function placental function and long-term cardio- metabolic effects on the progeny.

抽象的 胎盘是母亲和发育中的胎儿之间的门户。胎盘功能障碍会损害 胎儿生长并对后代产生长期影响，包括增加代谢疾病的风险。这 胎儿与母体沟通/交换的微妙平衡可能受到多种因素的影响，包括 母亲的饮食和疾病和/或接触内分泌干扰化合物 (EDC)。 EDC 是合成的 或干扰内分泌系统正常功能的天然化学物质，某些 EDC 具有 类固醇活性。胎儿接触此类 EDC 可能会对成人的健康构成威胁。现行政策规定 正在限制在消费品的制造过程中使用此类 EDC 之一——双酚 A (BPA)。 产品。新型、未经测试的工业化学替代品的出现，例如双酚 S (BPS)（一种 EDC） 与 BPA 相比，其与类固醇的亲和力非常明显，并且呈上升趋势。了解所带来的健康风险 新兴的 EDC 暴露至关重要。我们的初步研究使用绵羊作为体内模型和体外模型 使用人类细胞滋养层的研究表明，BPS 暴露会改变胎盘滋养层的功能。 BPA 不会导致相似的胎盘表型，凸显了不同胎盘之间关键且尚未探索的差异。 双酚 EDC。我们的初步数据表明 BPS 通过黄体酮受体介导其作用 途径。在我们的动物模型中，妊娠期 BPS 暴露也会影响胎儿大小并导致心脏代谢 干扰。本提案中描述的研究将利用胎儿-母体的独特动物模型 通讯、初级滋养层细胞和滋养层细胞系来测试新的假设 心脏代谢疾病的发育起源，特别强调了解分子机制 BPS 损害滋养层功能、胎盘功能和长期心脏功能的机制 对后代的代谢影响。