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

VATER相关性代表了一组脊椎、肛门、气管-食管、桡骨和肾脏畸形，而尾部退化综合征是由与泌尿生殖系统和下肢缺陷相关的下脊柱和髋关节的一系列先天性异常组成的实体。并发的各种畸形可能是由于一个共同的缺陷，在胚细胞，但直接的证据还有待积累。在这里，通过使用自体荧光和阿霉素的致畸作用，我们证明了阿霉素给药到白色来航鸡的鸡蛋分布到胚胎和前肠上皮的尾部，并诱导尾部退化和气管和肺发育不全。尾状回退综合征样异常的诱发具有发育阶段和剂量依赖性。尾部退化的胚胎表现出气管食管异常，其中一个缺陷包括在VATER协会。产生异常的阶段对应于人类胚胎在第22天和第26天之间的阶段（卡内基阶段10-11）。鉴于阿霉素通过嵌入到经历快速细胞分裂的未分化细胞的双链DNA中而具有抗肿瘤活性，阿霉素可能优先攻击尾端中的细胞，在该尾端中，在最大敏感性的狭窄时期期间发生显著增殖。

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.