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

描述(申请人提供)：越来越多的人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)是一种外来雌激素，在孕妇的血液中以每毫升纳克的水平循环。尽管如此，人们对其在人类发展方面的影响知之甚少。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，在动物身上的研究表明，这种环境中的化学物质会破坏胎盘形成，从而导致胎儿宫内发育受损。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都是在子宫中编程的。到目前为止，关于双酚A对人类胎盘影响的少量信息表明，有足够的理由感到担忧。现有的数据和我们的初步结果表明，这种环境化学作用于控制其正常发育和功能的途径的重要部分。我们小组研究人类胎盘已有多年。我们开发了一种支持从早期妊娠胎盘分离的原代细胞滋养层细胞(CTB)分化的体外模型。这种培养体系使我们能够研究CTB分化的重要调节分子，包括黏附分子、金属蛋白酶、转录因子和免疫分子的作用。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，以及与生长受损有关的异物的影响，如尼古丁。最近，我们建立了一个新的体外系统，使我们能够对人类胎盘形成的关键早期步骤进行建模。具体地说，我们从妊娠早期的胎盘中分离出了人滋养层祖细胞(TBPC)，这些细胞形成了在培养中持续自我复制的细胞系。分化后的细胞产生CTB和合体滋养层细胞(STB)。因此，这个模型使我们能够研究人类胎盘发育的基本方面，而这些方面以前是无法通过实验获得的。在这种情况下，我们假设双酚A暴露在母体血液和胎盘中测量的浓度范围内会损害人类胎盘形成的选择性方面。为了验证这一理论，我们将研究BPA对TBPC自我更新(目标1)以及向CTB和STB分化(目标2)的影响。我们预计，这些实验的结果将提供有关双酚A暴露对人类胎盘发育影响的重要数据。这些发现将使未来的实验能够通过研究从血双酚A水平已被测量的妇女身上收集的胎盘样本来确定这些变化在体内的相关性。

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.