Rengasamy Padmanabhan, Padmanabhan Rajagopala Ramanan
Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
Congenit Anom (Kyoto). 2004 Sep;44(3):156-71. doi: 10.1111/j.1741-4520.2004.00029.x.
In humans, the presence of cervical and lumbar ribs is of particular clinical significance. However, the relevance of their occurrence in the offspring of experimental animals in reproductive toxicologic studies is poorly understood. Maternal toxicity has been implicated in the etiology but conclusive evidence is lacking. The present study was undertaken to determine the incidence of supernumerary ribs (SNR) in mouse fetuses prenatally exposed to valproic acid (VPA) and retinoic acid (RA), and to compare their differential developmental susceptibility and morphological association with other axial skeletal anomalies. Single doses of valproic acid (VPA) or retinoic acid (RA) were administered to groups of mice on one of gestation days (GD) 7-12. Fetuses were collected on GD 18 and their skeletons examined for SNR. VPA treatment on GD 7 and GD 8 resulted in a high incidence of cervical and lumbar ribs, respectively. Cervical neural arch anomalies in the GD 7 group, and eight pairs of sternal ribs and seven sternebrae in the GD 8 group were observed in excess of the background SNR suggesting a direct effect of VPA on the developing mouse skeletal system. In the RA groups, GD 8-12 were susceptible for lumbar rib induction but increased incidence of cervical ribs was observed only from GD 9-12. Peak incidence of cervical ribs was found in the GD 10 and 11 groups and that of the lumbar ribs in the GD 8 and 11 groups. Although SNR incidence generally increased with increasing dose of RA, a strict dose-response relationship was lacking. Cervical arch anomalies were observed in as many embryos as those with cervical ribs, but eight pairs of sternal ribs and seven sternebrae did not correlate well with the lumbar ribs in the peak day groups. Interrupted cervical neural arches correlated well with lumbar ribs. The reduction in the frequency of presacral vertebrae from 26 to 25 in the VPA groups was limited to GD 7 (30%) and 8 (18%) groups. RA-induced reduction in presacral vertebral number extended to GD 9 and was greater in the GD 8 than in the GD 9 groups. Sternal anomalies occurred both in VPA and RA experiments and did not strictly correlate with the frequency of SNR. VPA had a narrow window of susceptibility, whereas RA effects on sternum extended from GD 9-12. The incidence of sternal anomalies generally increased with increasing dose and advancing developmental stage at which RA exposure occurred. These developmental susceptibility windows and associated malformations, when considered in the context of the ability of these drugs to induce alterations in gene expression in mouse embryos suggest that SNR are polygenic in origin and greatly influenced by environmental toxicants.
在人类中，颈椎肋和腰椎肋的存在具有特殊的临床意义。然而，在生殖毒理学研究中，它们在实验动物后代中的出现情况的相关性却鲜为人知。病因学中涉及母体毒性，但缺乏确凿证据。本研究旨在确定产前暴露于丙戊酸（VPA）和视黄酸（RA）的小鼠胎儿中多余肋骨（SNR）的发生率，并比较它们不同的发育易感性以及与其他轴骨骼异常的形态学关联。在妊娠第7至12天的某一天，对几组小鼠给予单剂量的丙戊酸（VPA）或视黄酸（RA）。在妊娠第18天收集胎儿，并检查其骨骼中的SNR。在妊娠第7天和第8天给予VPA处理分别导致颈椎肋和腰椎肋的高发生率。在妊娠第7天组中观察到颈椎神经弓异常，在妊娠第8天组中观察到八对胸骨肋和七个胸骨节超过背景SNR，这表明VPA对发育中的小鼠骨骼系统有直接影响。在RA组中，妊娠第8至12天易诱发腰椎肋，但仅从妊娠第9至12天观察到颈椎肋发生率增加。在妊娠第10和11天组中发现颈椎肋的发生率最高，在妊娠第8和11天组中发现腰椎肋的发生率最高。尽管SNR发生率通常随RA剂量增加而增加，但缺乏严格的剂量反应关系。观察到有颈椎肋的胚胎中出现颈椎弓异常的数量相同，但在高峰期组中，八对胸骨肋和七个胸骨节与腰椎肋的相关性不佳。中断的颈椎神经弓与腰椎肋相关性良好。VPA组中骶前椎骨数量从26减少到25仅限于妊娠第7天（30%）和第8天（18%）组。RA诱导的骶前椎骨数量减少扩展到妊娠第9天，且在妊娠第8天组中比妊娠第9天组中更明显。胸骨异常在VPA和RA实验中均有发生，且与SNR频率没有严格相关性。VPA的易感性窗口较窄，而RA对胸骨的影响从妊娠第9至12天。胸骨异常的发生率通常随剂量增加以及RA暴露时发育阶段的推进而增加。当考虑到这些药物在小鼠胚胎中诱导基因表达改变的能力时，这些发育易感性窗口和相关畸形表明SNR起源于多基因且受环境毒物的极大影响。
