Placental molecule secretions measured in early pregnancy are targets of endocrine disruption and are indicators of sex-specific fetal development.

妊娠早期测量的胎盘分子分泌物是内分泌干扰的目标，也是性别特异性胎儿发育的指标。

基本信息

批准号：
9320319
负责人：
Jennifer Joan Adibi
金额：
$ 15万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2018-08-31
项目状态：
已结题

项目摘要

The proposed project will use information from the placenta in early pregnancy (also called the gestational sac (GS)) to estimate environmental risks to the health of the newborn. According to population-wide biomonitor- ing studies, fetuses in the U.S. are exposed to a long list of endocrine disrupting chemicals (EDCs) that enter our bodies primarily through packaged and processed food and personal care product use. EDCs, such as phthalates and perfluoroalklyl chemicals (PFCs), can alter developmental pathways in the rodent fetus with consequences for the genitalia, brain, immune system, and body mass index. We have established a relation- ship using epidemiologic and experimental methods between phthalate exposures, sex-specific disruption of a placental hormone called human chorionic gonadotropin (hCG), and the distance between the anus and the genitalia in the newborns. Anogenital distance (AGD) is a marker of hormonal actions in utero and is predictive of fertility in the adult. Hence, we have offered a novel conceptual framework for the role of the early placenta or the gestational sac (GS) in endocrine disruption. We theorize that the role of the GS is distinct from the pla- centa proper, which forms at 10 weeks when maternal perfusion and nutrient transport begins. In this project we will extend this model to ask the question if the phthalate-hCG-genital relationship can be generalized to a) a class of persistent EDCs that also enter our bodies from processed and packaged food; b) a set of 5 other candidate molecules that are synthesized and secreted by the placenta and correlated with hCG; and c) other endpoints in the neonate that reflect sex-specific development. First, we will measure the real-time relationship between maternal exposures to endocrine disrupting compounds (EDC) in the earliest stage of pregnancy and their correlation with hormones and other molecules that are secreted and/or regulated by the GS. Secondly, we will measure outcomes in the male and female newborns that indicate differences in genital development, birth size, and adiposity or prenatal programming of obesity and other metabolic disorders. The outcomes in the neonates were selected, as they are predictive of longer-term health outcomes in the child and in the adult. Using statistical techniques, we will determine if the first trimester placental response to EDCs mediated the overall `effect' of the EDC exposure on neonatal outcomes. Thirdly, we will analyze the placental tissue (sam- pled at delivery) transcriptome for the global expression of coding and non-coding RNA levels. We will test the correspondence between the placental molecular signature (by sex and by phthalate) at the end of pregnancy with the placental secretion profile in early pregnancy. With these same data, we will test a hypothesis from our pilot studies on a specific type of epigenetic regulation of the transcriptome that may explain on a molecular level how phthalates induce a sex-specific response in the placenta. By testing a unified theory on the role of the GS, we will contribute to innovation in strategies to identify obstetric and developmental risks at early time points in pregnancy, and possibly within a timeframe to reduce risks to the child.

拟议的项目将在怀孕初期使用胎盘的信息（也称为妊娠囊（GS））估计新生儿健康的环境风险。根据人口范围的生物监测器 - ING研究，美国的胎儿暴露于一长串内分泌干扰化学物质（EDC）中我们的身体主要是通过包装和加工的食物和个人护理产品使用。 EDC，例如邻苯二甲酸盐和全氟化学物质（PFC）可以改变啮齿动物胎儿的发育途径生殖器，大脑，免疫系统和体重指数的后果。我们已经建立了一个关系 - 使用邻苯二甲酸酯暴露之间的流行病学和实验方法的船胎盘激素称为人绒毛膜促性腺激素（HCG），以及肛门与肛门之间的距离新生儿的生殖器。肛门生态距离（AGD）是子宫内激素作用的标志物，是预测性的成人的生育能力。因此，我们为早期胎盘的角色提供了一个新颖的概念框架或内分泌干扰中的妊娠囊（GS）。我们从理论上认为GS的作用与Pla-不同 centa适当，在孕产妇灌注和营养运输开始时，在10周形成。在这个项目中我们将扩展此模型，以询问一个问题，是否可以将邻苯二甲酸杆菌 - 生成关系推广到a）一类持久的EDC也从加工和包装的食物中进入我们的身体； b）其他5组由胎盘合成和分泌并与HCG相关的候选分子； c）其他新生儿的终点反映了性别特定的发展。首先，我们将衡量实时关系在最早的怀孕阶段，孕产妇暴露于内分泌破坏化合物（EDC）和它们与GS分泌和/或调节的激素和其他分子的相关性。第二，我们将衡量男性和女性新生儿的结果，这些新生儿表明生殖器发育差异，肥胖和其他代谢疾病的出生大小以及肥胖或产前编程。结果选择了新生儿，因为它们可以预测儿童和成人的长期健康结果。使用统计技术，我们将确定第一个三个月胎盘对EDC的反应是否介导 EDC暴露对新生儿结果的总体“影响”。第三，我们将分析胎盘组织（Sam- 在输送时提取）转录组，用于编码和非编码RNA水平的全局表达。我们将测试怀孕结束时的胎盘分子签名（通过性别和邻苯二甲酸盐）之间的对应关系怀孕初期的胎盘分泌物。通过这些相同的数据，我们将从我们的试点研究转录组的特定类型的表观遗传调节，该调节可以解释在分子上等级邻苯二甲酸如何在胎盘中诱导性别特异性反应。通过测试统一的理论 GS，我们将为识别早期识别产科和发展风险的战略创新做出贡献怀孕的点，甚至可能在时间范围内降低孩子的风险。