Fetal growth restriction triggered by polycyclic aromatic hydrocarbons is associated with altered placental vasculature and AhR-dependent changes in cell death
Fetal growth restriction triggered by polycyclic aromatic hydrocarbons is associated with altered placental vasculature and AhR-dependent changes in cell death
复制标题
DOI：
10.1152/ajpendo.90436.2008
复制
发表时间：
2008-08-01
影响因子：
5.1
通讯作者：
Jurisicova, Andrea
中科院分区：
文献类型：
--
作者：
Detmar, Jacqui;Rennie, Monique Y.;Jurisicova, Andrea
母亲吸烟被认为是与胎儿宫内生长受限(IUGR)相关的重要危险因素。多环芳烃(PAHs)是香烟烟雾中众所周知的成分，在不同的妊娠阶段急性暴露于这些化学物质的影响已经在各种实验动物中得到了很好的证实。此外，许多多环芳烃是芳香烃受体(AhR)的已知配体，AhR是一种负责激活新陈代谢机制的细胞异生传感器。在这项研究中，我们在受孕前对C57B1/6雌性小鼠应用了长期、低剂量的PAH暴露方案。这种治疗在胎盘后15.5天(d15.5)引起IUGR，并导致胎盘血管系统异常，导致胎盘动脉血管系统的动脉表面积和体积显著减少。然而，对暴露于PAH的大鼠胎盘迷路内的小血管的检查显示，这些血管有广泛的分支和增大，表明可能存在代偿机制。这些血管形成的改变伴随着胎盘细胞死亡率的降低，抗凋亡的XIAP表达水平的增加，以及促凋亡的Bax，裂解的聚(ADP-核糖)聚合酶-1和活性的caspase-3的表达降低。AHR缺陷的胎儿从PAH诱导的生长受限中解救出来，迷路细胞死亡率没有变化。这项研究的结果表明，长期接触多环芳烃是导致人类吸烟者宫内发育迟缓的一个因素，并参与了AhR途径。
Maternal cigarette smoking is considered an important risk factor associated with fetal intrauterine growth restriction (IUGR). Polycyclic aromatic hydrocarbons (PAHs) are well-known constituents of cigarette smoke, and the effects of acute exposure to these chemicals at different gestational stages have been well established in a variety of laboratory animals. In addition, many PAHs are known ligands of the aryl hydrocarbon receptor (AhR), a cellular xenobiotic sensor responsible for activating the metabolic machinery. In this study, we have applied a chronic, low-dose regimen of PAH exposure to C57B1/6 female mice before conception. This treatment caused IUGR in day 15.5 post coitum (d15.5) fetuses and yielded abnormalities in the placental vasculature, resulting in significantly reduced arterial surface area and volume of the fetal arterial vasculature of the placenta. However, examination of the small vasculature within the placental labyrinth of PAH-exposed dams revealed extensive branching and enlargement of these vessels, indicating a possible compensatory mechanism. These alterations in vascularization were accompanied by reduced placental cell death rates, increased expression levels of antiapoptotic Xiap, and decreased expression of proapoptotic Bax, cleaved poly(ADP-ribose) polymerase-1, and active caspase-3. AhR-deficient fetuses were rescued from PAH-induced growth restriction and exhibited no changes in the labyrinthine cell death rate. The results of this investigation suggest that chronic exposure to PAHs is a contributing factor to the development of IUGR in human smokers and that the AhR pathway is involved.