Environmental Stressors Impact Placentation Through Actions On Trophoblast, Immune, and Endothelial Cell Dynamics

Our environment is replete with chemicals that can affect embryonic and extraembryonic development. Dioxins, such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), are compounds affecting development through the aryl hydrocarbon receptor (AHR). TCDD exposures can lead to placental adaptations and at higher doses pregnancy termination. Deep intrauterine endovascular trophoblast cell invasion was a prominent placentation site adaptation to TCDD. TCDD-mediated placental adaptations were dependent upon maternal AHR signaling but not placental or fetal AHR nor the presence of a prominent AHR target, cytochrome P450 1A1 (CYP1A1). At the placentation site, TCDD stimulated CYP1A1 transcription within endothelial cells but not trophoblast cells. Immune and trophoblast cell behaviors at the uterine-placental interface were guided by the actions of TCDD on endothelial cells. In summary, we have identified an AHR regulatory pathway activated by environmental stressors affecting uterine and trophoblast cell dynamics and the formation of the hemochorial placenta.我们所处的环境中充斥着可影响胚胎发育与胚外发育的化学物质。二噁英（dioxins）类化合物，例如2,3,7,8-四氯二苯并对二噁英（2,3,7,8-tetrachlorodibenzodioxin, TCDD），可通过芳香烃受体（aryl hydrocarbon receptor, AHR）对发育过程产生影响。TCDD暴露可引发胎盘适应性改变，高剂量暴露时甚至会导致妊娠终止。宫内深部血管滋养层细胞侵袭是胎盘着床位点针对TCDD的显著适应性反应。TCDD介导的胎盘适应性改变依赖于母体的AHR信号通路，而非胎盘或胎儿的AHR，亦不依赖于经典AHR靶基因细胞色素P450 1A1（cytochrome P450 1A1, CYP1A1）。在胎盘着床位点，TCDD可刺激内皮细胞内的CYP1A1转录，但无法在滋养层细胞中实现该效应。子宫-胎盘界面处的免疫细胞与滋养层细胞行为，受TCDD作用于内皮细胞的过程调控。综上，本研究明确了一条由环境应激源激活的AHR调控通路，该通路可影响子宫与滋养层细胞的动态变化，并参与血绒毛膜胎盘（hemochorial placenta）的形成。