Endocrine Disruptors, Ahr Signaling, and Placentation

胎盘是成功怀孕的关键器官。胎盘发育涉及分化 滋养层干细胞分化为各种专门的滋养层细胞谱系，具有内分泌、运输和 子宫血管重塑功能。胎盘的形成是一个精心安排的 母体和胎儿组织之间的联系胎座形成的过程也具有可塑性。胎盘结构 和功能会受到环境挑战的影响。这些环境暴露包括 被称为内分泌干扰物的化学物质，干扰信号通路， 发育、生殖和免疫过程。胎盘作为生理屏障的作用 使其成为内分泌干扰物有害影响的脆弱目标。内分泌的影响 控制胎盘发育的调节过程的干扰物在很大程度上是未知的。我们假设 在发育的敏感和关键窗口期暴露于内分泌干扰物会影响胎盘 影响胎儿的生长和成熟，以及终生的产后健康。拟议 在实验中，我们将利用大鼠作为血绒膜胎盘形成的模型，并使用2，3，7，8-四氯二苯并 对二恶英（TCDD）和苯并[a]芘（BaP）作为模式内分泌干扰物。TCDD和BaP影响细胞 通过激活芳香烃受体途径发挥作用。我们将探讨内分泌的影响 干扰物，如TCDD和BaP和Ahr信号对血绒膜胎盘建立的影响， 大鼠作为动物模型。我们提出了两个目标：1）研究TCDD和BaP的作用， 胎盘发育2)评价母体与胎盘-胎儿TCDD和BAP作用影响的部位 胎盘发育这些努力将进一步加深我们对胎盘相关的病因学的理解 疾病，并提供了一个范式，为发展翻译的方法，以减轻有害影响的 内分泌干扰物对生殖健康的影响。

The placenta is a vital organ critical for a successful pregnancy. Placental development involves differentiation of trophoblast stem cells into various specialized trophoblast cell lineages with endocrine, transport, and uterine vascular remodeling functions. Formation of the placenta is a result of an orchestrated crosstalk between maternal and fetal tissues. The process of placentation also exhibits plasticity. Placental structure and function can be influenced by environmental challenges. These environmental exposures include chemicals known as endocrine disruptors that interfere with signaling pathways generating adverse effects on developmental, reproductive, and immunological processes. The role of the placenta as physiological barrier makes it a vulnerable target for the detrimental effects of endocrine disruptors. The effects of endocrine disruptors on regulatory processes controlling placental development are largely unknown. We hypothesize that exposure to endocrine disruptors at sensitive and critical windows of development will affect placental development, impacting growth and maturation of the fetus, and lifelong postnatal health. In the proposed experimentation, we will utilize the rat as a model of hemochorial placentation and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and benzo[a]pyrene (BaP) as a model endocrine disruptor. TCDD and BaP affect cellular function through activation of the aryl hydrocarbon receptor pathway. We will explore the impact of endocrine disruptors such as TCDD and BaP and Ahr signaling on establishment of the hemochorial placenta using the rat as an animal model. We propose two aims: 1) To investigate the actions of TCDD and BaP during placental development. 2) To evaluate maternal versus placental-fetal sites of TCDD and BAP action impacting placental development. These efforts will further our understanding of the etiology of placentation-related diseases and provide a paradigm for developing translational approaches to mitigate the detrimental effects of endocrine disruptors on reproductive health.