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

描述（由申请人提供）：人们越来越关注环境化学品对人类健康的影响。例如，公布的数据显示，双酚A (BPA)，一种雌激素，在孕妇血液中以每毫升纳克的水平循环。尽管如此，人们对它对人类发展的影响知之甚少。动物模型，主要是小鼠和大鼠，表明BPA对后代的一系列不良影响，从前列腺和乳腺异常到神经发育障碍。同样，动物研究表明，这种环境化学物质会破坏胎盘，从而导致宫内生长受损。后一项发现意义重大，因为大量证据表明，成人健康的许多重要参数是在子宫内编制的。迄今为止，关于双酚a对人类胎盘影响的少量已知信息表明，有充分的理由引起关注。现有数据和我们的初步结果表明，这种环境化学物质在控制其正常发育和功能的途径的重要部分起作用。我们研究人类胎盘已有多年。我们建立了一个体外模型，支持从妊娠早期胎盘分离的原代细胞滋养细胞（CTBs）的分化。该培养系统使我们能够研究包括粘附分子、金属蛋白酶、转录因子和免疫分子在内的重要CTB分化调节因子的作用。对正常过程的研究揭示了导致妊娠并发症的病理变化，如先兆子痫，以及与生长受损相关的外源性药物的影响，如尼古丁。最近，我们建立了一个新的体外系统，使我们能够模拟人类胎盘形成的关键早期步骤。具体来说，我们从早期妊娠胎盘中分离出人类滋养细胞祖细胞（TBPCs），这些细胞在培养中形成连续自我复制的细胞系。分化后，细胞产生CTBs和合胞滋养细胞（STBs）。因此，这个模型使我们能够研究人类胎盘发育的基本方面，这在以前是无法通过实验实现的。在这种情况下，我们假设在母体血液和胎盘中测量到的BPA暴露浓度范围损害了人类胎盘的选择性方面。为了验证这一理论，我们将研究BPA对TBPC自我更新（目标1）和CTBs和STBs分化（目标2）的影响。我们设想这些实验的结果将为BPA暴露对人类胎盘发育的影响提供重要的数据。这些发现将使未来的实验能够通过研究从血液中测量BPA水平的妇女身上收集的胎盘样本来确定这些改变的体内相关性。

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.