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Establishment of a rescue program for anorectal malformations induced by retinoic acid in mice
Yasunari Sasaki1, Naomi Iwai, Osamu Kimura
1Department of Pediatric Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. sasapon@koto.kpu-m.ac.jp
Aims Of Study:
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.
Conclusion:
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.
Insights
The retinoid antagonist LE135 can prevent anorectal malformations (ARMs) in mouse embryos exposed to retinoic acid. This finding offers potential strategies for protecting against human ARMs.
Area of Science:
- Developmental biology
- Teratology
- Molecular signaling
Background:
- Retinoic acid (RA) is vital for embryogenesis, controlling cell differentiation, morphogenesis, and apoptosis.
- RA receptors form heterodimers with retinoid X receptors to regulate gene expression.
- Previous studies demonstrated RA can induce anorectal malformations (ARMs) in mouse models.
Purpose of the Study:
- To investigate the efficacy of the retinoid antagonist LE135 in preventing RA-induced anorectal malformations (ARMs) in mouse embryos.
- To assess the impact of LE135 administration timing on ARM prevention.
Main Methods:
- Pregnant ICR strain mice were administered all-trans retinoic acid (RA) on embryonic day 9 (E9).
- The retinoid antagonist LE135 was administered on E8 (before RA) or E9 (simultaneously with RA).
- Embryos were collected on E18 and analyzed for anorectal malformations and tail development via histological examination.
Main Results:
- Administration of RA alone resulted in 100% of embryos exhibiting ARMs and tail absence.
- LE135 administration, either before or simultaneously with RA, significantly reduced ARM incidence (36% and 45% rescue rates, respectively).
- Rescued embryos in both LE135 groups exhibited shortened tails, indicating a partial developmental rescue.
Conclusions:
- The RAR-selective retinoid antagonist LE135 demonstrates a protective effect against RA-induced anorectal malformations in the developing hindgut of mouse embryos.
- The effectiveness of LE135 suggests a targeted approach to mitigating RA-induced developmental abnormalities.
- Further research in mouse models may inform strategies for preventing human anorectal malformations.
