Placental adaptive mechanisms to environmental exposures.

摘要 胎盘是母亲和发育中的胎儿之间的通道。胎盘功能障碍会损害 胎儿生长和诱导后代的长期影响，包括代谢疾病的风险增加。的 胎儿-母体沟通/交流的微妙平衡可能受到许多因素的影响，包括 母亲的饮食和疾病和/或暴露于内分泌干扰化合物（EDCs）。EDCs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， 类固醇活性。胎儿暴露于这些内分泌干扰物可能对成年人的健康构成威胁。现行政策法规 限制了此类内分泌干扰物之一双酚A（BPA）在消费品制造过程中的使用， 产品.新的、未经测试的工业化学品替代品的出现，如双酚S（BPS），一种EDC 与双酚A相比，具有非常明显的类固醇亲和力，正在上升。了解以下因素带来的健康风险 新出现的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， 使用人细胞滋养层的研究表明BPS暴露改变胎盘滋养层功能。 BPA不会导致类似的胎盘表型，突出了关键和未探索的差异， 双酚类内分泌干扰物。我们的初步数据表明，BPS介导其作用通过孕激素受体 通路在我们的动物模型中，妊娠期BPS暴露也会影响胎儿的大小，并导致心脏代谢异常。 干扰本提案中描述的研究将利用一种独特的胎-母动物模型， 通讯，原代滋养层细胞和滋养层细胞系，以测试一种新的假设， 心脏代谢紊乱的发育起源，特别强调理解分子 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。

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.