Nam C, Woo G H, Uetsuka K, Nakayama H, Doi K
Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
Histol Histopathol. 2006 Mar;21(3):257-63. doi: 10.14670/HH-21.257.
Etoposide (VP-16), a topoisomerase II inhibitor, is an anti-tumor agent which is also known to show embryotoxicity, and teratogenicity when administered to pregnant rodents. We examined VP-16-induced histopathological changes in the brain of mouse fetuses. Pregnant mice were intraperitoneally injected with VP-16 (4 mg/kg) on day 12 of gestation (GD 12), and fetuses were collected from 1 to 48 hours after treatment (HAT). Mitotic neuroepithelial cells in the telencephalic wall prominently decreased at 2 HAT, and were hardly observed at 4 HAT. The number of pyknotic neuroepithelial cells in the fetal brain began to increase at 4 HAT, and became prominent from 8 to 24 HAT. These pyknotic cells were also positively stained by TUNEL method, which can detect fragmented DNA, and showed ultrastructural characteristics of apoptosis. Additionally, these cells were also positive for cleaved caspase-3, an essential executioner of apoptosis. This indicated that excessive neuroepithelial cell apoptosis was induced in the brain of mouse fetuses following VP-16 treatment on GD 12.
依托泊苷（VP - 16）是一种拓扑异构酶II抑制剂，是一种抗肿瘤药物，已知在给怀孕啮齿动物用药时会表现出胚胎毒性和致畸性。我们研究了VP - 16诱导的小鼠胎儿大脑组织病理学变化。怀孕小鼠在妊娠第12天（GD 12）腹腔注射VP - 16（4 mg/kg），并在治疗后1至48小时（HAT）收集胎儿。端脑壁中的有丝分裂神经上皮细胞在治疗后2小时显著减少，在治疗后4小时几乎观察不到。胎儿大脑中固缩神经上皮细胞的数量在治疗后4小时开始增加，并在治疗后8至24小时变得明显。这些固缩细胞也被能检测DNA片段化的TUNEL法阳性染色，并表现出凋亡的超微结构特征。此外，这些细胞对凋亡的关键执行者裂解的半胱天冬酶 - 3也呈阳性。这表明在GD 12给予VP - 16治疗后，小鼠胎儿大脑中诱导了过度的神经上皮细胞凋亡。
