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

水关联是一组椎体、肛门、气管-食道、桡骨和肾脏畸形，尾侧退化综合征是由一系列与泌尿生殖系统和下肢缺陷相关的下脊柱和髋关节先天性异常组成的实体。多种畸形的同时发生可能是由一种常见的胚胎发育缺陷所解释的，但直接的证据尚未积累。在这里，通过使用自身荧光和阿霉素的致畸作用，我们证明了阿霉素给予白来角鸡的卵分布到胚胎的尾部和前肠上皮，并诱导尾部退化和气管和肺发育不全。尾侧退行综合征样异常的诱导是发育阶段和剂量依赖性的。胚胎尾部后退显示气管食管异常，其中一个缺陷包括在VATER协会。产生异常的阶段与人类胚胎在第22天和第26天的阶段相对应（卡内基阶段10-11）。鉴于阿霉素通过嵌入快速细胞分裂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细胞，在这段最敏感的狭窄时期，尾端细胞增殖明显。

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.