Adriamycin produces a reproducible teratogenic model of vertebral, anal, cardiovascular, tracheal, esophageal, renal, and limb anomalies in the mouse.
OBJECTIVE
The Adriamycin rat model is an established model for vertebral, anal, cardiac, tracheal, esophageal, renal, and limb (VACTERL) anomalies and gastrointestinal atresias. Mice are the foremost mammal studied by developmental biologists, providing greater availability of molecular probes, antibodies, and transferable knowledge with transgenic studies. Only tracheoesophageal malformations have been previously described in the Adriamycin mouse model. The aim of this study was to carry out a dose-response analysis of the teratogenicity of Adriamycin in the mouse to determine the effect of the dose and timing of exposure in producing tracheoesophageal malformations and show if it causes other VACTERL anomalies.


METHODS
CBA/Ca mice were accurately time mated (n = 30). Four different doses (0 [saline], 4, 5, and 6 mg/kg) of Adriamycin (EBEWE Pharma Ges.m.b.H. Nfg.KG, A-4866 Unterach, Austria) at 3 different timings of injections were compared. Dams received 2 intraperitoneal injections, 24 hours apart, commencing on day 7, 7.5, or 8. Fetuses were harvested on day 18. Anomalies were examined using a dissecting microscope and serial transverse sections.


RESULTS
Administering Adriamycin at 6 mg/kg on days 7 and 8 had the most teratogenic effect, with 80% of fetuses having 3 or more VACTERL anomalies: anorectal malformation, 100%; tracheoesophageal malformation, 50%; right-sided aortic arch, 58.3%; bladder agenesis/bilateral hydronephrosis, 100%.


CONCLUSIONS
This study establishes a mouse model that should provide insights into the cellular and molecular mechanisms underlying VACTERL anomalies.
Dawrant
Michael J
MJ
Department of Paediatric Surgery, National Children's Hospital, Tallaght, Dublin 24, Ireland.
Giles
Shay
S
Bannigan
John
J
Puri
Prem
P
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000015:Abnormalities, Multiple / Q000139:chemically induced* / Q000473:pathology; D001003:Anal Canal / Q000002:abnormalities / Q000196:embryology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004947:Esophagus / Q000002:abnormalities* / Q000196:embryology; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D006330:Heart Defects, Congenital / Q000139:chemically induced; D007668:Kidney / Q000002:abnormalities / Q000196:embryology; D017880:Limb Deformities, Congenital / Q000139:chemically induced; D051379:Mice; D008808:Mice, Inbred CBA; D023421:Models, Animal; D011247:Pregnancy; D011897:Random Allocation; D015203:Reproducibility of Results; D013045:Species Specificity; D013131:Spine / Q000002:abnormalities / Q000196:embryology; D013577:Syndrome; D014132:Trachea / Q000002:abnormalities* / Q000196:embryology
D004317:Doxorubicin