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.

抽象的 胎盘是母亲和发育中的胎儿之间的门户。胎盘功能障碍可能会损害 胎儿生长并诱导后代的长期影响，包括增加代谢疾病的风险。这 胎儿沟通 /交流的微妙平衡可能会受到许多因素的影响 孕产妇饮食和疾病和 /或暴露于内分泌干扰化合物（EDC）。 EDC是合成的 或天然化学物质会干扰某些EDC的内分泌系统正常功能 类固醇活性。胎儿接触此类EDC会对成人福祉构成威胁。当前的政策法规 在消费者的制造过程中，限制了这种EDCS，双酚A（BPA）的使用 产品。新的，未经测试的工业化学替代品的出现，例如双球醇S（BPS），EDC 与BPA相比，具有非常不同的类固醇亲和力正在上升。了解健康风险 新兴的EDC暴露至关重要。我们使用绵羊作为体内模型和体外的初步研究 使用人类细胞增生细胞的研究表明，BPS暴露会改变胎盘滋养细胞的功能。 BPA不会导致类似的胎盘表型，突出显示了关键和未开发的差异 双苯酚EDC。我们的初步数据表明，BPS通过孕酮受体介导其作用 路径。在我们的动物模型中，妊娠BPS暴露还会影响胎儿的大小，并导致心脏代谢 干扰。该提案中描述的研究将利用feto-Mentnal的独特动物模型 交流，原代滋养细胞和滋养细胞细胞系，以检验新的假设 心脏代谢疾病的发育起源，特别强调分子 BPS损害滋养细胞功能胎盘功能和长期心脏 - 代谢对后代的影响。