Cadmium-induced teratogenicity: Association with ROS-mediated endoplasmic reticulum stress in placenta
Cadmium-induced teratogenicity: Association with ROS-mediated endoplasmic reticulum stress in placenta
复制标题
镉诱导的致畸性：与胎盘中 ROS 介导的内质网应激的相关性
DOI：
10.1016/j.taap.2012.01.001
复制
发表时间：
2012-03-01
影响因子：
3.8
通讯作者：
Xu, De-Xiang
中科院分区：
文献类型：
--
作者：
Wang, Zhen;Wang, Hua;Xu, De-Xiang
胎盘对于维持胎儿的生长是必不可少的。内质网(ER)压力的增加与胎盘和胎儿发育受损有关。镉(Cd)是一种能引起胎儿畸形和生长受限的致畸物质。本研究调查了母亲镉暴露对胎盘和胎儿发育的影响。孕鼠于妊娠第9天腹腔注射氯化镉(4.5 mg/kg)。不出所料，母亲在肢体发育早期暴露于镉可显著增加胎儿前肢指趾的发生率。经氯化镉处理的小鼠胎盘迷路明显受损，迷路是一种高度发达的血管组织。此外，母体镉暴露显著抑制胎盘细胞增殖和增加细胞凋亡。另一项实验表明，母亲镉暴露显著上调了内质网伴侣蛋白GRP78的表达。此外，母亲镉暴露诱导了胎盘elF2α的磷酸化，这是PERK信号的下游分子。此外，母体镉暴露显著增加了胎盘CHOP的水平，这是PERK信号的另一个靶点，表明Cd处理的小鼠胎盘中的未折叠蛋白反应(UPR)信号被激活。有趣的是，α-苯基-N-叔丁基硝酮，一种自由基自旋捕捉剂，显著缓解了镉诱导的胎盘ER应激和UPR。综上所述，这些结果提示，活性氧(ROS)介导的内质网应激可能参与了镉对胎盘和胎儿发育的损害。抗氧化剂可以作为药理药物来保护镉引起的胎儿畸形和生长受限。(C)2012 Elsevier Inc.保留所有权利。
The placenta is essential for sustaining the growth of the fetus. An increased endoplasmic reticulum (ER) stress has been associated with the impaired placental and fetal development. Cadmium (Cd) is a potent teratogen that caused fetal malformation and growth restriction. The present study investigated the effects of maternal Cd exposure on placental and fetal development. The pregnant mice were intraperitoneally injected with CdCl2 (4.5 mg/kg) on gestational day 9. As expected, maternal Cd exposure during early limb development significantly increased the incidences of forelimb ectrodactyly in fetuses. An obvious impairment in the labyrinth, a highly developed tissue of blood vessels, was observed in placenta of mice treated with CdCl2. In addition, maternal Cd exposure markedly repressed cell proliferation and increased apoptosis in placenta. An additional experiment showed that maternal Cd exposure significantly upregulated the expression of GRP78, an ER chaperone. Moreover, maternal Cd exposure induced the phosphorylation of placental elF2 alpha, a downstream molecule of PERK signaling. In addition, maternal Cd exposure significantly increased the level of placental CHOP, another target of PERK signaling, indicating that the unfolded protein response (UPR) signaling was activated in placenta of mice treated with CdCl2. Interestingly, alpha-phenyl-N-t-butylnitrone, a free radical spin-trapping agent, significantly alleviated Cd-induced placental ER stress and UPR. Taken together, these results suggest that reactive oxygen species (ROS)-mediated ER stress might be involved in Cd-induced impairment on placental and fetal development. Antioxidants may be used as pharmacological agents to protect against Cd-induced fetal malformation and growth restriction. (C) 2012 Elsevier Inc. All rights reserved.