A multiple retinoic acid antagonist induces conotruncal anomalies, including transposition of the great arteries, in mice

Daria Cipollone, Francesca Amati, Rita Carsetti, Silvia Placidi, Michela Biancolella, Giulia D'Amati, Giuseppe Novelli, Gregorio Siracusa, Bruno Marino

Research output: Contribution to journalArticle

Abstract

Background: The morphogenetic mechanisms that are responsible for the transposition of the great arteries are still largely unknown, mainly because this malformation is very difficult to experimentally reproduce. The aim of the present study was to test the effect of BMS-189453, a retinoic acid antagonist, on murine heart morphogenesis. Methods: We administered this drug at 5 mg/kg body weight (twice, at a 12-h interval) to pregnant mice on 6.25/6.75 days postcoitum (dpc) (Group A), 6.75/7.25 dpc (Group B), 7.25/7.75 dpc (Group C), 7.75/8.25 dpc (Group D), or 8.25/8.75 dpc (Group E). At birth, the anatomical features of fetuses were evaluated by stereomicroscopic examination. Results: In Group A (18 fetuses), cardiovascular anatomy was normal in 10 (56%) cases, and 8 (44%) fetuses presented with transposition of the great arteries. In Group B, no fetuses were obtained. In Group C (78 fetuses), cardiovascular anatomy was normal in 19 (24%) cases, while 59 (76%) mice presented with various types of cardiac defects, including 48 transpositions of the great arteries (61%). In Group D (80 fetuses), cardiac defects were seen in 22 (27%) mice: 14 of these (17%) were transpositions of the great arteries. In Group E (72 fetuses), cardiovascular anatomy was normal in all cases. Of 248 fetuses analyzed, 87% presented with thymic aplasia or hypoplasia, and 20% presented with meroanencephalia and/or rachischisis. Conclusions: Transposition of the great arteries can be consistently reproduced in mice by administration of a retinoic acid competitive antagonist on 7.5 dpc.

Original languageEnglish
Pages (from-to)194-202
Number of pages9
JournalCardiovascular Pathology
Volume15
Issue number4
DOIs
Publication statusPublished - Jul 2006

Keywords

  • BMS-189453
  • Heart defects
  • Retinoic acid
  • Transposition of the great arteries

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pathology and Forensic Medicine

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