Impaired distribution of retinoic acid receptors in the hindgut-tailgut region of murine embryos with anorectal malformations

Background/Purpose: Retinoid-mediated signal transduction plays a crucial r ole in the organogenesis of various organs. To investigate the pathogenesis of anorectal malformations (ARM), the authors studied the distribution pat tern of retinoic acid receptors (RARs) in ARM murine embryos induced by ove rdose of all-trans retinoic acid (ATRA). Methods: Pregnant mice were gavage-fed 100 mg/kg of ATRA on the ninth gesta tional day (E9.0). Embryos were obtained between E11.0 and E14.0 and were f ixed immediately in a 4% paraformaldehyde solution. Frozen sections were pr epared for immunohistochemistry using antibodies specifically raised agains t RAR-alpha, RAR-beta, and RAR-gamma. Results: Over 98% of the embryos administered ATRA had ARM; rectoprostatic urethral and rectocloacal fistulas were the most frequent anomalies. The im munoreactivity of RAR-alpha was found equally in the epithelium of hindgut- tailgut in normal embryos on E11.5. However, it was absent in the hindgut i n the treated embryos, The immunoreactivities of RAR-beta and RAR-gamma sho wed no difference in the distal hindgut. Conclusions: Impaired distribution of RAR-alpha in the hindgut-tailglut on E11.5 resulted in the incomplete partitioning of the cloaca and the rectour ethral or rectocloacal fistula on E14.0. These results suggest that overdos e of ATRA affects the distal hindgut development by directly disrupting the retinoid-mediated signalling pathway. Copyright (C) 2001 by W.B. Saunders Company.