A multiple retinoic acid antagonist induces conotruncal anomalies, including transposition of the great arteries, in mice.
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.
Cipollone
Daria
D
Department of Public Health and Cell Biology, University of Rome Tor Vergata, 00173 Rome, Italy.
Amati
Francesca
F
Carsetti
Rita
R
Placidi
Silvia
S
Biancolella
Michela
M
D'Amati
Giulia
G
Novelli
Giuseppe
G
Siracusa
Gregorio
G
Marino
Bruno
B
D000014:Abnormalities, Drug-Induced / Q000473:pathology*; D000818:Animals; D005260:Female; D005327:Fetal Resorption; D005333:Fetus / Q000187:drug effects; D005865:Gestational Age; D006321:Heart / Q000187:drug effects* / Q000196:embryology; D051379:Mice; D011247:Pregnancy; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D012176:Retinoids / Q000633:toxicity*; D014188:Transposition of Great Vessels / Q000139:chemically induced* / Q000473:pathology
C423184:BMS 189453; D018168:Receptors, Retinoic Acid; D012176:Retinoids