Environmental Exposures, AHR Activation, and Placental Origins of Development

项目总结/摘要 血绒膜胎座发生在许多哺乳动物物种中，包括灵长类动物和啮齿动物。它确保 最密切的接触之间的母亲和胚胎室，并需要专门的调整 在怀孕期间胎盘发育和功能的中断会影响胎儿健康，并导致 成人疾病的起源我们的环境是化学物质和有毒物质的来源，它们会影响细胞和 分子过程，包括那些控制血绒膜胎盘的形态发生和功能。 环境暴露的时间可能是决定其对胎盘形成和产后影响的关键 健康环境暴露的化学性质是广泛的，并决定细胞和分子 应答多氯联苯（PCBs）作为工业的副产品被释放到环境中 并且当在产前引入时具有影响胚胎和胎盘发育的能力。芳基 碳氢化合物受体（AHR）是对多种物质敏感的分子途径的关键组成部分 外源性暴露（包括多氯联苯），并在胎盘形成部位起作用。AHR与AHR相互作用 核转运子（ARNT）调节大量编码酶的基因的转录， 在环境污染物的生物转化、代谢和解毒中起重要作用的转运蛋白等。 污染物在AHR靶基因中有细胞色素P450 1A 1（CYP 1A 1）。CYP 1A 1可以催化 外源性和内源性底物的生物转化，这可能有助于整体 外源性物质对胎盘发育的作用机制。暴露于环境对 胎盘发育受到了有限的实验关注。我们方法的基础是， 环境暴露对胎座形成的作用具有保守性。我们在这项研究中的努力 建议包括与相关动物模型，大鼠和组织的互补和互动努力， 人类怀孕的标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期研究环境暴露对发育的影响， 血绒膜胎盘我们的重点是对异生素作用（AHR）的信号转导通路，而不是 任何一个特定的暴露。目的No.1利用大鼠模型和滋养层干细胞研究其机制 与外源性激活的AHR信号对大鼠胎盘发育的影响相关，并将在 堪萨斯大学医学中心，堪萨斯城，而Aim No.2利用人胎盘组织 标本和怀孕的人类受试者研究与异生物质激活AHR相关的机制 人类胎盘发育的信号，并将在儿童慈善堪萨斯城进行。 在“生理学背景”下理解胎盘发育的关键分子机制是 确定易受环境因素调节失调影响的相关发育敏感事件 暴露。

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.