Adriamycin-Induced Models of VACTERL Association

Abstract

Animal models are of great importance for medical research. They have enabled analysis of the aetiology and pathogenesis of complex congenital malformations and have also led to major advances in the surgical and therapeutic management of these conditions. Animal models allow us to comprehend the morphological and molecular basis of disease and consequently to discover novel approaches for both surgical and medical therapy. The anthracycline antibiotic adriamycin was incidentally found to have teratogenic effects on rats, producing a range of defects remarkably similar to the VACTERL association of congenital anomalies in humans, providing a reproducible animal model of this condition. VACTERL association is a spectrum of birth defects which includes vertebral, anal, cardiovascular, tracheo-oesophageal, renal and limb anomalies. In recent years, adriamycin rodent models of VACTERL have provided valuable insights into the pathogenesis of this complex association, particularly in relation to tracheo-oesophageal malformations. The adriamycin rat model and adriamycin mouse model are now well established in the investigation of the morphology of faulty organogenesis and the regulation of gene expression in tracheo-oesophageal anomalies.

Patterns of malformation associated with esophageal atresia/tracheoesophageal fistula: A retrospective single center study

“…EA/TEF can also be part of the VACTERL or VATER association, an acronym that refers to the nonrandom occurrence of V ertebral defects, A nal atresia, C ardiac , T racheo‐ E sophageal fistula, R enal and L imb defects (Nora & Nora, 1975; Solomon, 2011; Temtamy & Miller, 1974). The etiology of nonsyndromic EA/TEF is still unknown, a variety of genetic (Brosens, de Jong, et al, 2014; Shaw‐Smith, 2006) and environmental (Felix et al, 2008; Mc Laughlin, Hajduk, Murphy, & Puri, 2013) factors have been proposed. While familial isolated EA/TEF cases have been infrequently reported (Pletcher, Friedes, Breg, & Touloukian, 1991), large studies have shown a very low recurrence risk for isolated EA/TEF among first degree relatives (Bartels et al, 2012; Choinitzki et al, 2013).…”

Esophageal atresia and prenatal exposure to mycophenolate

“…Experimental studies in rats and mice have shown that doxorubicin can cause atresia of esophagus. Also, considering the presence of other abnormalities in animals, it has been suggested that this drug may cause a clinical picture remarkably similar to the VACTERL association in humans [18]. However, human prenatal exposure to doxorubicin has not been associated with esophageal atresia.…”

Sonic Hedgehog, VACTERL, and Fanconi anemia: Pathogenetic connections and therapeutic implications

“…Tracheo‐esophageal anomalies occur in 28–93% of treated rat embryos, the majority the same form as the most common human type. For the urogenital system, abnormalities such as renal agenesis that occur in humans can be seen [Mc Laughlin et al, ], but most renal findings are secondary to absence of the bladder [Temelcos and Hutson, ], which is not common with VACTERL. The most frequent cardiac finds were ventricular and atrial septal defects, and a right‐sided aortic arch and a patent ductus arteriosus were also increased [Qi et al, ]. Human FA pathway genes: In 1927, Guido Fanconi reported on three brothers with short stature, hypogonadism, skin pigmentation, and childhood deaths from aplastic anemia, a condition subsequently named for him.…”