Environmental Exposures, AHR Activation, and Placental Origins of Development

项目摘要/摘要 血液胎盘存在于许多哺乳动物物种中，包括灵长类和啮齿动物。它确保了 母体和胚胎之间最密切的接触，需要专门的调整 在怀孕期间。胎盘发育和功能紊乱会影响胎儿健康，并导致 成人疾病的起源。我们的环境是化学物质和毒物的来源，它们可以影响细胞和 分子过程，包括那些控制血色胎盘的形态发生和功能的过程。 环境暴露的时间可能是决定其对胎盘和出生后影响的关键 健康。环境暴露的化学性质是广泛的，并决定了细胞和分子 回应。多氯联苯作为工业副产品排放到环境中。 在产前引入时，会影响胚胎和胎盘的发育。芳香族 碳氢化合物受体(AHR)是一种对多种生物敏感的分子途径的重要组成部分 异种生物暴露(包括多氯联苯)和在胎盘部位手术。AHR与AHR交互 核转运蛋白(ARNT)调节编码酶基因的转录， 转运蛋白等在环境生物转化、新陈代谢和解毒中的重要作用 污染物。AHR的靶基因包括细胞色素P450 1A1(CYP1A1)。细胞色素P450 1A1可以催化 外源和内源底物的生物转化，这可能有助于 异种生物作用于胎盘发育的机制。环境暴露对人类健康的影响 胎盘发育在实验上受到的关注有限。我们方法的基础是 环境暴露对胎盘形成的作用具有保守性。我们在这项研究中所做的努力 建议包括与相关动物模型、大鼠和组织的互补和互动努力 人类怀孕的样本。我们将运用我们在发育生物学、毒理学、 毒理基因组学和围产学，以调查环境暴露对糖尿病发展的影响 血色胎盘。我们的重点是响应外源生物作用的信号通路(AHR)，而不是 任何一次特定的接触。目的1号利用大鼠模型和滋养层干细胞来研究机制 与异种生物激活的AHR信号对大鼠胎盘发育的影响有关，并将在 堪萨斯城的堪萨斯大学医学中心，而AIM 2号使用的是人类胎盘组织 研究异种激活的AHR的相关机制 关于人类胎盘发育的信号，将在堪萨斯城儿童慈悲医院进行。 了解在“生理环境”中对胎盘发育至关重要的分子机制是 确定易受环境失调影响的相关发展敏感事件 曝光。

PROJECT SUMMARY/ABSTRACT Hemochorial placentation occurs in many mammalian species including primates and rodents. It ensures the most intimate contact between maternal and embryonic compartments and requires specialized adjustments during gestation. Disruptions in placental development and function affect fetal health and contribute to the origins of adult disease. Our environment is a source of chemicals and toxicants that can affect cellular and molecular processes, including those controlling the morphogenesis and function of the hemochorial placenta. Timing of environmental exposures are likely critical in determining their effects on placentation and postnatal health. Chemical properties of environmental exposures are wide-ranging and dictate cellular and molecular responses. Polychlorinated biphenyls (PCBs) are released into the environment as a byproduct of industry and when introduced prenatally have the capacity to influence embryonic and placental development. The aryl hydrocarbon receptor (AHR) is a key component of a molecular pathway sensitive to a wide range of xenobiotic exposures (including PCBs) and operative at the placentation site. AHR interacts with the AHR nuclear translocator (ARNT) to regulate transcription of an expansive cadre of genes encoding enzymes, transporters, etc. important in the biotransformation, metabolism, and detoxification of environmental pollutants. Among the AHR target genes is cytochrome P450 1A1 (CYP1A1). CYP1A1 can catalyze the biotransformation of both exogenous and endogenous substrates, which may contribute to the overall mechanism of xenobiotic action on placenta development. The impact of environmental exposures on placental development has received limited experimental attention. The foundation of our approach is that there is conservation in the actions of environmental exposures on placentation. Our efforts in this research proposal include complementary and interactive efforts with a relevant animal model, the rat, and with tissue specimens from human pregnancies. We will apply our expertise in developmental biology, toxicology, toxicogenomics, and perinatology to investigate the effects of environmental exposures on development of the hemochorial placenta. Our focus is on a signaling pathway responsive to xenobiotic action (AHR) rather than any one specific exposure. Aim No.1 utilizes rat models and trophoblast stem cells to investigate mechanisms associated with xenobiotic activated AHR signaling on rat placental development and will be performed at the University of Kansas Medical Center, Kansas City, whereas Aim No. 2 utilizes human placental tissue specimens and pregnant human subjects to investigate mechanisms associated with xenobiotic activated AHR signaling on human placental development and will be conducted at Children’s Mercy Kansas City. Understanding molecular mechanisms critical for placental development in a “physiological context” is a key to identifying relevant developmentally sensitive events that are susceptible to dysregulation by environmental exposures.