Dose response relationship between adriamycin and birth defects in a rat model of VATER association.
OBJECTIVE
The aim of this study was to reproduce the animal model of esophageal atresia and the VATER association. The purpose was a dose response analysis of Adriamycin teratogenicity in the rat and comparison of these anomalies with the human VATER association.


METHODS
Twenty time-mated Sprague-Dawley rats received intraperitoneal Adriamycin (dose range, 0 to 2.5 mg/kg/d) for 4 consecutive gestational days E6 to E9. The embryos were harvested on day E21, inspected, weighed, and dissected with a binocular dissecting microscope. Statistical analysis was performed with exact chi2.


RESULTS
Threshold doses of 1.25 and 1.5 mg/kg/d Adriamycin produced renal and gastrointestinal anomalies, respectively (exact chi2, P < .00001). In doses below 1.25 mg/kg/d Adriamycin, no anomalies were seen, and in above-threshold doses, the frequency of anomalies rose sharply as the dose increased. At 2.25 mg/kg/d of Adriamycin all embryos were abnormal, and Adriamycin at 2.5 mg/kg/d led to resorption of all embryos.


CONCLUSIONS
Adriamycin induced esophageal atresia, and VATER in the rat is a reproducible model that has many similarities to the VATER anomalies in the human. There is a relationship between dose and the frequency as well as severity of anomalies. Further studies of this model are likely to provide information relevant to the understanding of this human congenital disease.
Orford
J E
JE
Department of Surgical Research, Royal Alexandra Hospital for Children, Westmead, NSW, Australia.
Cass
D T
DT
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000015:Abnormalities, Multiple / Q000139:chemically induced*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004933:Esophageal Atresia / Q000139:chemically induced*; D005260:Female; D006801:Humans; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
D004317:Doxorubicin