Department of Pediatric Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
J Pediatr Surg. 2011 Jul;46(7):1396-9. doi: 10.1016/j.jpedsurg.2010.10.011.
Retinoid-mediated signal transduction plays a crucial role in the embryogenesis of various organs. We previously reported the successful induction of anorectal malformations in mice using retinoic acid (RA). Retinoic acid controls the expression of essential target genes for cell differentiation, morphogenesis, and apoptosis through a complicated interaction in which RA receptors form heterodimers with retinoid X receptors. In the present study, we investigated whether the retinoid antagonist, LE135, could prevent the induction of anorectal malformations (ARMs) in mice.
Retinoic acid was intraperitoneally administered as 100 mg/kg of all-trans RA on E9; and then the retinoid antagonist, LE135, was intraperitoneally administered to pregnant ICR strain mice on the eighth gestational day (E8), 1 day before administration of RA (group B) or on E9, simultaneously (group C) with RA administration. All of the embryos were obtained from the uteri on E18. Frozen sections were evaluated for concentric layers around the endodermal epithelium by hematoxylin and eosin staining.
In group A, all of the embryos demonstrated ARM with rectoprostatic urethral fistula, or rectocloacal fistula, and all of the embryos showed the absence of a tail. In group B, 36% of the embryos could be rescued from ARM. However, all of the rescued embryos had a short tail that was shorter than their hind limb. The ARM rescue rates in group B were significantly improved compared to those in group A (P < .01). In group C, 45% of the embryos were rescued from ARM, but all of the rescued embryos had short tail. The ARM rescue rate in group C was significantly improved compared to that in group A (P < .01). However, there was no significant difference in the ARM rescue rate between group B and Group C.
The present study provides evidence that in the hindgut region, RAR selective retinoid antagonist, LE135, could rescue embryos from ARM. However, the disturbance of all-trans RA acid was limited to the caudal region. Further study to establish an appropriate rescue program for ARM in a mouse model might suggest a step toward protection against human ARM in the future.
视黄酸（RA）介导的信号转导在各种器官的胚胎发生中起着至关重要的作用。我们之前曾报道过使用视黄酸（RA）成功诱导小鼠发生肛门直肠畸形（ARM）。RA 通过 RA 受体与视黄酸 X 受体形成异二聚体的复杂相互作用，控制细胞分化、形态发生和凋亡的必需靶基因的表达。在本研究中，我们研究了视黄酸拮抗剂 LE135 是否可以预防小鼠发生肛门直肠畸形（ARM）。
在 E9 时，将 100mg/kg 的全反式 RA 经腹腔内给予；然后，在 RA 给药前一天（第 8 天，E8）或同时（第 9 天，E9）给予妊娠 ICR 品系小鼠腹腔内给予视黄酸拮抗剂 LE135。所有胚胎均于 E18 从子宫中取出。通过苏木精和伊红染色对冷冻切片进行评估，以观察围绕内胚层上皮的同心层。
在 A 组中，所有胚胎均表现出直肠前列腺尿道瘘或直肠会阴瘘，所有胚胎均无尾巴。在 B 组中，36%的胚胎可免于 ARM。然而，所有获救的胚胎尾巴都很短，比后肢短。B 组的 ARM 挽救率明显高于 A 组（P<.01）。在 C 组中，45%的胚胎免于 ARM，但所有获救的胚胎尾巴都很短。C 组的 ARM 挽救率明显高于 A 组（P<.01）。然而，B 组和 C 组的 ARM 挽救率无显著差异。
本研究提供的证据表明，在回肠区域，RAR 选择性视黄酸拮抗剂 LE135 可以使胚胎免于 ARM。然而，全反式 RA 酸的干扰仅限于尾侧区域。进一步的研究可能会建立一种适当的小鼠模型中 ARM 挽救方案，为未来人类 ARM 的预防提供了一种途径。
Zotero 插件