Environmental Exposures, AHR Activation, and Placental Origins of Development

环境暴露、AHR 激活和胎盘发育起源

• 批准号: 10176489
• 负责人: Elin Grundberg
• 金额: $ 52.16万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176489
• 关键词: ARNT gene; ARNT protein; Affect; Animal Model; Aryl Hydrocarbon Receptor; Attention; Barker Hypothesis; CYP11A1 gene; CYP1A1 gene; Chemicals; Child; Cities; Development; Developmental Biology; Diagnostic; Disease; Dissection; Drug Metabolic Detoxication; Embryo; Embryonic Development; Endocrine disruption; Ensure; Environment; Environmental Exposure; Environmental Impact; Environmental Pollutants; Enzymes; Etiology; Event; Fetal health; Foundations; Functional disorder; Genes; Genetic Determinism; Genetic Transcription; Health; Hemochorial Placental Development; Human; Industry; Kansas; Medical center; Metabolic Biotransformation; Metabolism; Missouri; Modeling; Molecular; Morphogenesis; Pathway interactions; Perinatology; Physiological; Placenta; Placentation; Polychlorinated Biphenyls; Pregnancy; Pregnancy Outcome; Primates; Process; Rattus; Receptor Activation; Receptor Signaling; Research Proposals; Rodent; Role; Signal Pathway; Site; Source; Specimen; Structure; Therapeutic; Tissues; Toxicogenomics; Toxicology; Universities; Xenobiotics; chemical property; human subject; insight; postnatal; pregnant; prenatal; response; toxicant; trophoblast stem cell

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.

项目摘要/摘要 血液体位置发生在许多哺乳动物物种中，包括素数和啮齿动物。它确保了 母体和胚胎隔室之间的最亲密接触，需要专门的调整 在妊娠期间。位置发育和功能的破坏会影响胎儿健康，并有助于 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，可能影响细胞和 分子过程，包括控制血解度plapeta的形态发生和功能的过程。 环境暴露的时间对于确定其对安置和产后的影响可能至关重要 健康。环境暴露的化学特性是大范围的，决定了细胞和分子 回答。多氯联苯（PCB）被释放到环境中，作为工业的副产品 当引入产前时，具有影响胚胎和胎盘发育的能力。芳基 碳氢化合物受体（AHR）是分子途径对广泛范围敏感的关键组成部分 异种生物暴露（包括PCB）并在位置部位运行。 AHR与AHR互动 核转运剂（ARNT）调节编码酶的额外基因干部的转录， 转运蛋白等对环境的生物转化，代谢和解毒的重要 污染物。在AHR靶基因中，有细胞色素P450 1A1（CYP1A1）。 CYP1A1可以催化 外源和内源性底物的生物转化，这可能有助于总体 异种生物作用对PLACETA发育的机制。环境暴露对 胎盘发育受到了有限的实验关注。我们方法的基础是 环境暴露对安置的行动有保护。我们在这项研究中的努力 建议包括与相关动物模型，大鼠和组织的完整和互动式努力 人类怀孕的标本。我们将应用我们的发育生物学，毒理学， 毒理基因组学和截骨学研究环境暴露对发展的影响 胎儿胎盘。我们的重点是响应异种动作（AHR）的信号通路，而不是 任何一个特定的曝光。 AIM 1使用大鼠模型和滋养细胞干细胞来研究机制 与异种生物激活的AHR信号有关在大鼠位置发育中的AHR信号传导，并将在 堪萨斯城堪萨斯大学医学中心 标本和孕妇的受试者研究与异种生物激活的AHR相关的机制 关于人类占地开发的信号，将在儿童慈悲堪萨斯城进行。 理解在“生理环境”中对位置发育至关重要的分子机制是关键的关键 识别相关的发展敏感事件，这些事件容易受到环境失调的影响 暴露。