Placental adaptive mechanisms to environmental exposures.

胎盘对环境暴露的适应机制。

基本信息

批准号：
10414993
负责人：
Almudena Veiga-Lopez
金额：
$ 34.87万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-11-19 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414993
关键词：
Address Adult Adverse effects Affect Affinity Animal Model Asthma Blood Circulation Canada Cardiometabolic Disease 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

项目摘要

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。