Menegola E, Broccia M L, Prati M, Giavini E
Department of Biology, University of Milan, Italy.
Teratology. 1999 Feb;59(2):110-9. doi: 10.1002/(SICI)1096-9926(199902)59:2<110::AID-TERA5>3.0.CO;2-2.
The antiepileptic drug valproic acid is a well-known teratogenic agent; its main target organ is the neural tube, though skeletal malformations have also been described. In our recent work, respecifications of vertebrae were described in rat fetuses after treatment with 400 mg/kg of sodium valproate at specific somitogenic stages. The observed malformations were stage-dependent. Morphological segmental respecification was observed at the level of segments in formation at the moment of exposure and at the level of more posterior segments. Recently, specific alterations in the development of cranial nerves and ganglia were described in mouse embryos after in vitro exposure to VPA. The aim of the present work was to analyze dysmorphogenetic effects of VPA on embryonic metameric structures: somites, spinal and cranial nerves, and ganglia. Sodium valproate (400 mg/kg) was subcutaneously injected at specific gestational times corresponding to embryonic stages: presomitic or at about 2, 6, 10, 14, 18, or 22 somites. Females were sacrificed on the day 12 post coitum, and embryos were examined. Morphological examination of somites was performed by staining with acridine orange. Morphological examination of nerves and ganglia was performed by immunostaining, using monoclonal antibodies to the 160-kD neurofilament protein. No abnormalities were observed in the cranial nerves and ganglia. Specific and stage-dependent alterations were observed both at the level of the somites and at the level of the spinal nerves. The following characteristic malformations were observed: fusions, duplications, and reductions of somites and corresponding spinal nerves and ganglia. Our morphological data suggest a morphogenetic action of VPA at the level of the axial segments, with a possible respecification of the identity of the interested segments and their derivatives.
抗癫痫药物丙戊酸是一种众所周知的致畸剂；其主要靶器官是神经管，不过也有骨骼畸形的相关报道。在我们最近的研究中，描述了在特定体节发生阶段用400mg/kg丙戊酸钠处理后大鼠胎儿椎骨的重新指定情况。观察到的畸形具有阶段依赖性。在暴露时正在形成的节段水平以及更靠后的节段水平观察到了形态学上的节段重新指定。最近，在体外暴露于丙戊酸的小鼠胚胎中描述了颅神经和神经节发育的特定改变。本研究的目的是分析丙戊酸对胚胎分节结构（体节、脊神经和颅神经以及神经节）的致畸作用。在与胚胎阶段相对应的特定妊娠期皮下注射丙戊酸钠（400mg/kg）：前体节期或大约有2、6、10、14、18或22个体节时。在交配后第12天处死雌性大鼠，并检查胚胎。通过吖啶橙染色对体节进行形态学检查。通过免疫染色，使用针对160-kD神经丝蛋白的单克隆抗体对神经和神经节进行形态学检查。在颅神经和神经节中未观察到异常。在体节水平和脊神经水平均观察到了特定的且具有阶段依赖性的改变。观察到以下特征性畸形：体节以及相应的脊神经和神经节的融合、重复和减少。我们的形态学数据表明丙戊酸在轴节段水平具有形态发生作用，可能会对相关节段及其衍生物的身份进行重新指定。
