A Novel Model for Assessing the Effects of BPA Exposures on Human Placentation

评估 BPA 暴露对人体胎位影响的新模型

基本信息

批准号：
8249353
负责人：
SUSAN J. FISHER
金额：
$ 23.49万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8249353
关键词：
Activins Adult Affect Animal Model Animals Area Aryl Hydrocarbon Receptor Binding Biological Markers Blood Cell Adhesion Molecules Cell Culture System Cell Culture Techniques Cell Differentiation process Cell Line Cell Separation Cells Chorion Commit Data Decision Making Development Differentiation Antigens Dose Embryonic Development Endocrine Disruptors Estrogen Receptors Estrogens Experimental Models Exposure to Familiarity Family member Female Fetal Growth Fibroblast Growth Factor 2 Future Gelatin Gene Expression Profiling Generations Goals Growth Growth Factor Health High Prevalence Human Human Development Immune In Vitro Insulin Investigation Lead Maintenance Mammary gland Maternal-Fetal Exchange Measures Mediating Membrane Metalloproteases Modeling Mus Neurodevelopmental Disorder Nicotine Nodal Nuclear Receptors Organ Orphan Pathway interactions Peroxisome Proliferators Placenta Placentation Play Policies Population Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Outcome Pregnant Women Primary Cell Cultures Process Prolactin Prostate Publications Publishing Rattus Research Design Risk Role Sampling Seminal Series Signal Transduction Somatotropin Staging Stem cells Stratification Study models Syncytiotrophoblast System Testing Transformed Cell Line Villus Woman Work Xenobiotics adipocyte differentiation bisphenol A cytotrophoblast environmental chemical estrogen-related receptor in utero in vitro Model in vitro testing in vivo inhibitor/antagonist insight interest male milliliter novel offspring progenitor programs receptor research study self-renewal sex theories transcription factor trophoblast xenoestrogen

项目摘要

DESCRIPTION (provided by applicant): Concern is growing about the effects of environmental chemicals on human health. For example, published data show that bisphenol A (BPA), a xenoestrogen, circulates at nanogram per milliliter levels in the blood of pregnant women. Despite this fact, very little is known about its effects in terms of human development. Animal models, primarily mice and rats, suggest an array of untoward effects of BPA on the offspring that range from prostate and mammary gland abnormalities to neurodevelopmental disorders. Similarly, studies in animals suggest that this environmental chemical disrupts placentation, which results in impaired intrauterine growth. The latter finding is significant because a great deal of evidence suggests that many important parameters of adult health are programmed in utero. To date, the small amount of information that is known about BPA effects on the human placenta suggests there is ample cause for concern. Available data and our preliminary results show this environmental chemical acts in important parts of the pathways that govern its normal development and functions. Our group has studied human placentation for many years. We developed an in vitro model that supports differentiation of primary cytotrophoblasts (CTBs) isolated from early gestation placentas. This culture system has allowed us to study the role of important regulators of CTB differentiation including adhesion molecules, metalloproteinases, transcription factors, and immune molecules. Studying the normal process has revealed the pathological changes that contribute to pregnancy complications, such as preeclampsia, and the effects of xenobiotics that are associated with impaired growth, such as nicotine. Very recently we established a new in vitro system that allows us to model the critical early steps in formation of the human placenta. Specifically, we isolated human trophoblast progenitor cells (TBPCs) from early gestation placentas that form lines that continuously self-replicate in culture. Upon differentiation, the cells give rise to CTBs and syncytiotrophoblasts (STBs). Therefore, this model allows us to study fundamental aspects of human placental development that were previously inaccessible to experimentation. In this context, we hypothesize that BPA exposures in a range of concentrations that have been measured in maternal blood and placentas impair selective aspects of human placentation. To test this theory, we will study the effects of BPA on TBPC self-renewal (Aim 1) and differentiation to CTBs and STBs (Aim 2). We envision that the results of these experiments will provide important data regarding the consequences of BPA exposures on human placental development. These findings will enable future experiments to determine the in vivo relevance of these alterations by studying placental samples collected from women whose blood levels of BPA have been measured. PUBLIC HEALTH RELEVANCE: The effects of environmental chemicals on human health, especially endocrine disruptors, are an important area of investigation. In this context, the goal of this proposal is to study the effects of bisphenol A (BPA) exposures on human placentation. These experiments will employ a new cell culture model for studying human placental development, trophoblast progenitor cells (TBPCs). The approach is to determine BPA effects on TBPC self-renewal (Aim 1) and differentiation to cytotrophoblasts and syncytiotrophoblasts (Aim 2), which will enable identification of the major pathways that this environmental chemical disrupts.

描述（由申请人提供）：关注环境化学物质对人类健康的影响。例如，发表的数据表明，双酚A（BPA）是一种异雌激素，在孕妇血液中以每毫升水平的纳米级循环。尽管这一事实，但对人类发展的影响知之甚少。动物模型（主要是小鼠和大鼠）提出了BPA对后代的一系列不良影响，范围从前列腺和乳腺异常到神经发育障碍。同样，对动物的研究表明，这种环境化学化学会破坏胎盘，从而导致宫内生长受损。后一个发现很重要，因为大量证据表明，子宫内编程了许多成人健康的重要参数。迄今为止，有关BPA对人体胎盘影响的少量信息表明，人们有充分关注的理由。可用的数据和我们的初步结果表明，这种环境化学作用在控制其正常发育和功能的途径的重要部分。我们的小组研究了人类胎盘多年。我们开发了一种体外模型，该模型支持从早期妊娠胎盘中分离出的原代细胞质细胞（CTB）的分化。该培养系统使我们能够研究CTB分化重要调节剂的作用，包括粘附分子，金属蛋白酶，转录因子和免疫分子。研究正常过程已经揭示了导致妊娠并发症的病理变化，例如先兆子痫以及与生长受损相关的异生元的作用，例如尼古丁。最近，我们建立了一个新的体外系统，使我们能够建模人体胎盘形成的关键早期步骤。具体而言，我们从早期的妊娠胎盘中分离了人类滋养细胞祖细胞（TBPC），这些胎盘形成了在培养中持续自我复制的线条。分化后，细胞会产生CTB和合成型成素细胞（STB）。因此，该模型使我们能够研究人类胎盘发育的基本方面，这些方面以前无法实验无法访问。在这种情况下，我们假设BPA暴露于在母体血液和胎盘中测量的一系列浓度，会损害人胎盘的选择性方面。为了检验这一理论，我们将研究BPA对TBPC自我更新（AIM 1）以及与CTB和STB（AIM 2）的影响。我们设想这些实验的结果将提供有关BPA暴露对人胎盘发育的后果的重要数据。这些发现将使未来的实验通过研究从BPA血液水平的女性中收集的胎盘样本来确定这些改变的体内相关性。公共卫生相关性：环境化学物质对人类健康，尤其是内分泌破坏者的影响是重要的调查领域。在这种情况下，该提案的目的是研究双酚A（BPA）暴露对人胎盘的影响。这些实验将采用一种新的细胞培养模型来研究人胎盘发育，滋养细胞祖细胞（TBPC）。该方法是确定BPA对TBPC自我更新的影响（AIM 1），并分化了对细胞增生细胞和合成型成素细胞的影响（AIM 2），这将使能够鉴定这种环境化学化学的主要途径。