Identifying the mechanism of VATER association by developmental-stage specific administration of adriamycin

Vater关联代表一组脊柱、肛门、气管-食道、放射状和肾脏畸形，而尾部退行性综合征是一种实体，由一系列与泌尿生殖系统和下肢缺陷相关的下脊柱和髋部先天性异常组成。多种畸形并存的原因可能是原始细胞发生中的一个共同缺陷，但直接证据尚待积累。本文利用自体荧光技术和阿霉素的致畸作用，证明了阿霉素作用于白来亨虫卵的尾部和前肠上皮，可导致尾部退化和气管、肺发育不全。尾部退行性综合征样异常的诱导具有发育阶段和剂量依赖性。尾部退化的胚胎显示出气管-食道异常，这是Vater关联的缺陷之一。产生异常的阶段与人类胚胎在第22-26天(卡内基阶段10-11)的阶段一致。鉴于阿霉素通过插入处于快速分裂过程中的未分化细胞的双链DNA而具有抗肿瘤活性，阿霉素可能优先攻击尾端的细胞，在这一最敏感的狭窄时期，细胞发生显著的增殖。

VATER association represents a cluster of Vertebral, Anal, Tracheo-Esophageal, Radial and Renal malformations, and caudal regression syndrome is an entity consisting of a spectrum of congenital anomalies of lower spine and hips ssociated with genitourinary and lower limb defects. The concurrence of various malformations may be explained by a common defect in blastogenesis, but direct evidence is yet to be accumulated. Here, by the use of autofluorescence and the teratogenic effect of adriamycin, we demonstrated that adriamycin administered to eggs of White Leghorns distributes to the caudal portion of the embryo and foregut epithelium and induces caudal regression and tracheal and pulmonary agenesis. The induction of caudal regression syndrome-like anomaly was developmental stage and dose dependent. Embryos with caudal regression demonstrated tracheoesophageal anomalies, one of the defects included in VATER association. The stages at which anomalies were produced corresponded to that of human embryos between days 22 and 26 (Carnegie stages 10-11). In view of the antitumor activity of adriamycin by intercalating to double-stranded DNA of undifferentiated cells undergoing rapid cell division, it is possible that adriamycin had preferentially attacked cells in the caudal end where pronounced proliferation takes place during this narrow period of greatest susceptibility.