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Skeletal malformations associated with esophageal atresia: clinical and experimental studies
H Xia1, L Migliazza, S Montedonico
1Department of Pediatric Surgery, Hospital Universitario La Paz, Madrid, Spain.
Insights
Prenatal Adriamycin exposure in rats caused esophageal atresia (EA) and skeletal malformations, including vertebral and limb defects, similar to those seen in human EA patients. This validates the rat model for studying EA and associated anomalies.
Area of Science:
- Developmental biology
- Teratology
- Congenital malformations
Background:
- Esophageal atresia (EA) is frequently associated with skeletal malformations in human infants.
- Investigating the etiology of these combined defects is crucial for understanding developmental processes.
Purpose of the Study:
- To determine if prenatal exposure to Adriamycin, a known teratogen, induces skeletal defects in rat fetuses similar to those observed in human EA patients.
- To validate a rat model for studying the pathogenesis of EA and associated anomalies.
Main Methods:
- Retrospective review of skeletal malformations in 443 human infants with EA.
- Induction of EA in rat fetuses via intraperitoneal Adriamycin administration on gestational days 8 and 9.
- Skeletal analysis of control and experimental rat fetuses using alcian blue and alizarin red staining.
Main Results:
- Human infants with EA exhibited a high incidence (55%) of skeletal malformations, including vertebral segmentation and identity defects, and limb anomalies.
- Adriamycin-exposed rat fetuses showed high rates of EA (62%) along with vertebral anomalies (e.g., butterfly vertebrae) and limb ossification delays or malformations.
- While not identical, the nature of skeletal defects in Adriamycin-induced EA rats showed significant similarities to human EA cases.
Conclusions:
- Prenatal Adriamycin exposure is a valid method for inducing EA and associated skeletal malformations in rat fetuses.
- The observed vertebral and limb defects in the rat model closely resemble those found in human infants with EA.
- This Adriamycin-induced rat model serves as a valuable tool for further research into the mechanisms underlying EA and its concurrent malformations.
Background/Purpose:
Patients with esophageal atresia (EA) often have skeletal malformations. The purpose of this study is to examine if similar defects occur in rat fetuses prenatally exposed to Adriamycin, a chemical capable of causing EA in these animals.
Methods:
The charts of 443 babies with EA were reviewed to assess the incidence and nature of these defects in them. Time-mated female rats were given either 2 mg/kg intraperitoneal Adriamycin (experimental group, n = 16) or no treatment (control group, n = 4) on gestational days 8 and 9, and the fetuses were removed near term. Skeletal anatomy was studied after alcian blue and alizarin red staining.
Results:
A total of 528 skeletal malformations, mainly abnormal segmentation and vertebral identity (extra or defective bodies or ribs), mishaped vertebral bodies, and limb malformations like radial aplasia or hypoplasia were found in 245 babies (55%). Costal fusion and sternal anomalies were present in 17 and 4 babies, respectively. In the animal study, all control fetuses were normal, whereas 83 of 134 experimental fetuses (62%) had EA accompanied by other malformations. No segmentation or vertebral identity anomalies were seen, but butterfly, wedged, and asymmetric vertebral bodies were found at various levels in all animals with EA and in about half of those without it. Three fetuses had rib anomalies, and 3 more had sternal malformations. Ossification of limbs was delayed in treated fetuses and short, thick, and crooked bones were seen in 4 of 31 fetuses with EA and in none of the Adriamycin-exposed ones without EA.
Conclusions:
Adriamycin exposure induces in fetal rats, in addition to esophageal, duodenal, and anorectal atresias, high proportions of vertebral malformations and some limb defects of nature not identical but quite similar to that of babies with EA. This further validates this model for investigating the nature of the processes leading to EA and its associated malformations.