Placental adaptive mechanisms to environmental exposures.

胎盘对环境暴露的适应机制。

• 批准号: 10378855
• 负责人: Almudena Veiga-Lopez
• 金额: $ 7.44万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-19 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378855
• 关键词: Adult; Affect; Affinity; Animal Model; Cardiometabolic Disease; Cell Line; Cells; Chemicals; Communication; Data; Development; Disease; Endocrine Disruptors; Endocrine system; Environmental Exposure; Equilibrium; Exposure to; Fetal Development; Fetal Growth Retardation; Functional disorder; Health; Human; In Vitro; Industrialization; Long-Term Effects; Mediating; Metabolic Diseases; Molecular; Mothers; Outcome; Pathway interactions; Personal Satisfaction; Phenotype; Placenta; Policies; Pregnancy; Progesterone Receptors; Regulation; Risk; Sheep; Steroids; Testing; bisphenol A; cardiometabolism; chemical substitution; consumer product; cytotrophoblast; fetal; in vivo; in vivo Model; manufacturing process; mother nutrition; novel; prenatal exposure; trophoblast

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.

摘要 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 并对后代产生长期影响，包括增加患代谢性疾病的风险。这个 母胎沟通/交换的微妙平衡可能会受到许多因素的影响，包括 母亲的饮食和疾病和/或接触内分泌干扰物(EDCs)。EDC是人工合成的 或干扰内分泌系统正常功能的天然化学物质，一些内分泌细胞具有 类固醇活性。胎儿暴露在这样的EDCs中可能会对成年人的健康构成威胁。现行政策法规 正在限制其中一种EDCs，双酚A(BPA)在消费者的制造过程中的使用 产品。新的、未经测试的工业化学替代品的出现，如双酚S(BPS)，一种EDC 与双酚A相比，类固醇的亲和力非常明显，正在上升。了解以下物质构成的健康风险 新兴的EDC风险敞口至关重要。绵羊作为体内和体外模型的初步研究 使用人细胞滋养层细胞的研究表明，BPS暴露改变了胎盘滋养层细胞的功能。 BPA不会导致类似的胎盘表型，突出了关键的和未探索的差异 双酚类EDCs。我们的初步数据表明，BPS通过孕激素受体介导其作用。 路径。在我们的动物模型中，孕期BPS暴露也会影响胎儿的大小并导致心脏代谢 干扰。这项提案中描述的研究将利用一种独特的母胎动物模型 通信、原代滋养层细胞和滋养层细胞系来检验一种新的假说 心脏代谢紊乱的发育起源，特别强调对分子的理解 BPS影响滋养细胞功能、胎盘功能和长期心脏功能的机制 代谢对后代的影响。