title: Establishment of a rescue program for anorectal malformations induced by retinoic acid in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatric Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. sasapon@koto.kpu-m.ac.jp
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Naomi
authors.initials: N
authors.lastname: Iwai
authors.forename: Osamu
authors.initials: O
authors.lastname: Kimura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ono
authors.forename: Tomoki
authors.initials: T
authors.lastname: Tsuda
authors.forename: Eiichi
authors.initials: E
authors.lastname: Deguchi
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000209:etiology / Q000517:prevention & control*; D000015:Abnormalities, Multiple / Q000139:chemically induced / Q000196:embryology / Q000517:prevention & control*; D001003:Anal Canal / Q000002:abnormalities*; D000818:Animals; D002988:Cloaca / Q000002:abnormalities / Q000196:embryology; D003984:Dibenzazepines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D005402:Fistula / Q000139:chemically induced / Q000196:embryology / Q000517:prevention & control; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D023421:Models, Animal; D011247:Pregnancy; D011469:Prostatic Diseases / Q000139:chemically induced / Q000196:embryology / Q000517:prevention & control; D011897:Random Allocation; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D012003:Rectal Fistula / Q000139:chemically induced / Q000196:embryology / Q000517:prevention & control; D012007:Rectum / Q000002:abnormalities*; D013045:Species Specificity; D013623:Tail / Q000002:abnormalities; D014212:Tretinoin / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D003984:Dibenzazepines; C104182:LE 135; D018168:Receptors, Retinoic Acid; D014212:Tretinoin