Hutt Karla J, Shi Zhanquan, Albertini David F, Petroff Brian K
Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
BMC Dev Biol. 2008 Jan 2;8:1. doi: 10.1186/1471-213X-8-1.
Environmental toxicants, whose actions are often mediated through the aryl hydrocarbon receptor (AhR) pathway, pose risks to the health and well-being of exposed species, including humans. Of particular concern are exposures during the earliest stages of development that while failing to abrogate embryogenesis, may have long term effects on newborns or adults. The purpose of this study was to evaluate the effect of maternal exposure to the AhR-specific ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the development of rat pre-implantation embryos with respect to nuclear and cytoskeletal architecture and cell lineage allocation.
We performed a systematic 3 dimensional (3D) confocal microscopy analysis of rat pre-implantation embryos following maternal exposure to environmentally relevant doses of TCDD. Both chronic (50 ng/kg/wk for 3 months) and acute (50 ng/kg and 1 mug/kg at proestrus) maternal TCDD exposure disrupted morphogenesis at the compaction stage (8-16 cell), with defects including monopolar spindle formation, f-actin capping and fragmentation due to aberrant cytokinesis. Additionally, the size, shape and position of nuclei were modified in compaction stage pre-implantation embryos collected from treated animals. Notably, maternal TCDD exposure did not compromise survival to blastocyst, which with the exception of nuclear shape, were morphologically similar to control blastocysts.
We have identified the compaction stage of pre-implantation embryogenesis as critically sensitive to the effects of TCDD, while survival to the blastocyst stage is not compromised. To the best of our knowledge this is the first in vivo study to demonstrate a critical window of pre-implantation mammalian development that is vulnerable to disruption by an AhR ligand at environmentally relevant doses.
环境毒物的作用通常通过芳烃受体（AhR）途径介导，对包括人类在内的受暴露物种的健康和福祉构成风险。特别令人担忧的是在发育的最早阶段的暴露，虽然不会消除胚胎发生，但可能对新生儿或成年人产生长期影响。本研究的目的是评估母体暴露于AhR特异性配体2,3,7,8-四氯二苯并对二恶英（TCDD）对大鼠植入前胚胎发育的影响，涉及核和细胞骨架结构以及细胞谱系分配。
我们对母体暴露于环境相关剂量TCDD后的大鼠植入前胚胎进行了系统的三维（3D）共聚焦显微镜分析。母体TCDD的慢性暴露（50 ng/kg/周，持续3个月）和急性暴露（在动情前期分别为50 ng/kg和1 μg/kg）均在致密化阶段（8-16细胞）破坏形态发生，缺陷包括单极纺锤体形成、f-肌动蛋白帽化以及由于异常胞质分裂导致的片段化。此外，从处理动物收集的致密化阶段植入前胚胎中，细胞核的大小、形状和位置发生了改变。值得注意的是，母体TCDD暴露并未影响囊胚的存活，除了核形状外，囊胚在形态上与对照囊胚相似。
我们已确定植入前胚胎发生的致密化阶段对TCDD的影响极为敏感，而囊胚阶段的存活不受影响。据我们所知，这是第一项体内研究，证明了植入前哺乳动物发育的一个关键窗口期易受环境相关剂量的AhR配体破坏。
