Abstract
Esophageal atresia (EA) is often associated with cardiovascular and other malformations that are likely neural crest derived. The present study tests the hypothesis that the heart and great vessels and the thymus and parathyroids may be abnormal in the rat model of EA as a result of disturbed neural crest development. Time-mated pregnant rats received intraperitoneally on d 8 and 9 of gestation either 2 mg/kg adriamycin or vehicle. Esophageal, heart, and thymic malformations were sought under the microscope in term fetuses. The parathyroids were histologically investigated. Control fetuses had no malformations, whereas 69 of 109 fetuses exposed to adriamycin had EA and 45 of 69 had 15 right aortic arches, nine aberrant right subclavia, eight ventricular septal defects, six narrow pulmonary outflow tracts, five tetralogies of Fallot, three double outflow right ventricles, three double aortic arches, three atrial septal defects, three right ductus arteriosus, and two truncus. The thymus was absent in 19, hypoplastic in 12, and ectopic in five out of 36 fetuses with EA in which it was studied, whereas the parathyroid glands were absent in 16, single in four, and ectopic in one of the 23 fetuses with EA in which they were studied. In conclusion, the nature of the cardiovascular, thymic, and parathyroid malformations associated with EA in rats is consistent with the hypothesis of neural crest participation in their pathogenesis. Mechanisms simultaneously disturbing foregut septation, somitic segmentation, and neural crest development should be sought to explain the combined occurrence of malformations in EA.
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Abbreviations
- EA:
-
esophageal atresia
- CVM:
-
cardiovascular malformation
- VSD:
-
ventricular septal defect
- TOF:
-
tetralogy of Fallot
- NPOT:
-
narrow pulmonary outflow tract
- DORV:
-
double outlet right ventricle
- TA:
-
truncus arteriosus
- ASD:
-
atrial septal defect
- RAA:
-
right aortic arch
- ARSA:
-
aberrant right subclavian artery
- DAA:
-
double aortic arch
- RDA:
-
right ductus arteriosus
- CoA:
-
coarctation of the aorta
- PDA:
-
persistent ductus arteriosus
References
Russell LJ, Weaver DD, Bull MJ 1981 The axial mesodermal dysplasia spectrum. Pediatrics 67: 176–182
Weaver DD, Mapstone CL, Yu PL 1986 The VATER association. Am J Dis Child 140: 225–229
Cozzi F, Myers NA, Madonna S, Drago S, Fiocca G, Piacenti S, Pierro A 1991 Esophageal atresia, choanal atresia, and dysautonomia. J Pediatr Surg 26: 548–552
Cozzi F, Myers NA, Piacenti S, Orfei P, Cozzi DA, Bonanni M, Madonna L 1993 Maturational dysautonomia and facial anomalies associated with esophageal atresia: support for neural crest involvement. J Pediatr Surg 28: 798–801
Hiyama E, Yokohama T, Ichikawa T, Miyamoto K, Matsuura Y 1990 CHARGE association with neuroblastoma. Pediatr Surg Int 5: 463–465
Kutiyanawala M, Wyse RK, Brereton RJ, Spitz L, Kiely EM, Drake D, Blake K 1992 CHARGE and esophageal atresia. J Pediatr Surg 27: 558–560
German JC, Mahour GH, Woolley MM 1976 Esophageal atresia and associated anomalies. J Pediatr Surg 11: 299–306
Greenwood RD, Rosenthal A 1976 Cardiovascular malformations associated with tracheoesophageal fistula and esophageal atresia. Pediatrics 57: 87–91
Chittmittrapap S, Spitz L, Kiely EM, Brereton RJ 1989 Oesophageal atresia and associated anomalies. Arch Dis Child 64: 364–368
Ein SH, Shandling B, Wesson D, Filler RM 1989 Esophageal atresia with distal tracheoesophageal fistula: associated anomalies and prognosis in the 1980s. J Pediatr Surg 24: 1055–1059
Mee RBB, Beasley SW, Auldist AW, Myers NA 1992 Influence of congenital heart disease on management of oesophageal atresia. Pediatr Surg Int 7: 90–93
Rokitansky A, Kolankaya A, Bichler B, Mayr J, Menardi G 1994 Analysis of 309 cases of esophageal atresia for associated congenital malformations. Am J Perinatol 11: 123–128
Palacios J, Gamallo C, Garcia M, Rodriguez JI 1993 Decrease in thyrocalcitonin-containing cells and analysis of other congenital anomalies in 11 patients with DiGeorge anomaly. Am J Med Genet 46: 641–646
Diez-Pardo JA, Qi B, Navarro C, Tovar JA 1996 A new rodent experimental model of oesophageal atresia and tracheo-oesophageal fistula: preliminary report. J Pediatr Surg 31: 498–502
Qi BQ, Diez-Pardo J, Navarro C, Tovar JA 1996 Narrowing the embryologic window of the adriamycin-induced fetal rat model of esophageal atresia and tracheo-esophageal fistula. Pediatr Surg Int 11: 444–447
Qi BQ, Merei J, Farmer P, Hasthorpe S, Myers NA, Beasley SW, Hutson JM 1997 Cardiovascular malformations in rat fetuses with oesophageal atresia and tracheo-oesophageal fistula induced by adriamycin. Pediatr Surg Int 12: 556–564
Xia H, Migliazza L, Montedonico S, Rodriguez JI, Diez-Pardo JA, Tovar JA 1999 Skeletal malformations associated with esophageal atresia: clinical and experimental studies. J Pediatr Surg 34: 1385–1392
Merei J, Hasthorpe S, Farmer P, Hutson JM 1999 Visceral anomalies in prenatally adriamycin-exposed rat fetuses: a model for the VATER association. Pediatr Surg Int 15: 11–16
Qi BQ, Merei J, Farmer P, Hasthorpe S, Myers NA, Beasley SW, Hutson JM 1997 The vagus and recurrent laryngeal nerves in the rodent experimental model of esophageal atresia. J Pediatr Surg 32: 1580–1586
Cheng W, Bishop AE, Spitz L, Polak JM 1999 Abnormal enteric nerve morphology in atretic esophagus of fetal rats with adriamycin-induced esophageal atresia. Pediatr Surg Int 15: 8–10
Qi BQ, Uemura S, Farmer P, Myers NA, Hutson JM 1999 Intrinsic innervation of the oesophagus in fetal rats with oesophageal atresia. Pediatr Surg Int 15: 2–7
Davies MRQ 1996 Anatomy of the extrinsic nerve supply of the oesophagus in oesophageal atresia of the common type. Pediatr Surg Int 11: 230–233
Hokama A, Myers NA, Kent M, Campbell PE, Chow CW 1986 Esophageal atresia with tracheo-esophageal fistula: a histopathological study. Pediatr Surg Int 1: 117–121
Ein SH, Izukawa T, Su WJ, Cook D, Stephens A, Rowe RD 1998 The influence of cardiovascular malformations on the prognosis of esophageal atresia and distal tracheoesophageal fistula. Pediatr Surg Int 4: 318–321
Muraji T, Mahour GH 1984 Surgical problems in patients with VATER-associated anomalies. J Pediatr Surg 19: 550–554
Corsello G, Maresi E, Corrao AM, Dimita U, Lo Cascio M, Cammarata M, Giuffre L 1992 VATER/VACTERL association: clinical variability and expanding phenotype including laryngeal stenosis. Am J Med Genet 44: 813–815
Iuchtman M, Brereton R, Spitz L, Kiely EM, Drake D 1992 Morbidity and mortality in 46 patients with the VACTERL association. Isr J Med Sci 28: 281–284
Huang LW, Chen MR, Lin SP, Huang FY, Ho MY, Kao HA, Hsu CH, Huung HY, Tsai TC 1995 The VATER association: analysis of forty-six cases without karyotyping. PMID 36: 30–34
Jones MC 1990 The neurocristopathies: reinterpretation based upon the mechanism of abnormal morphogenesis. Cleft Palate J 27: 136–140
Pagon RA, Graham JM, Zonana J, Yong SL 1981 Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 99: 223–227
Larsen WJ 1997 Human Embryology, 2nd Ed. Churchill Livingstone, New York, pp 189–196
Olson EN, Srivastava E 1996 Molecular pathways controlling heart development. Science 272: 671–676
Kirby ML, Waldo KL 1990 Role of the neural crest in congenital heart disease. Circulation 82: 332–340
Kirby ML, Waldo KL 1995 Neural crest and cardiovascular patterning. Circ Res 77: 211–215
Schweitzer VG, Clack TD 1984 Waardenburg's syndrome: a case report with CT scanning and cochleovestibular evaluation. Int J Pediatr Otorhinolaryngol 7: 311–322
Schenk VWD, Geene MJ, Klein HW, Kredeit P, Stefanko S 1976 A human embryo of 28-mm crown-rump length with cerebral, esophagotracheal, and cardiovascular malformations. Anat Embryol 150: 53–62
Greene EC 1963 Anatomy of the Rat. Hafner Publishing Company, NY and London, pp 109–112
Hoskins MM, Chandler SB 1925 Accessory parathyroids in the rat. Anat Rec 30: 95–99
Possoegel AK, Diez-Pardo JA, Morales C, Navarro C, Tovar JA 1998 Embryology of esophageal atresia in the adriamycin rat model. J Pediatr Surg 33: 606–612
Kaufman MH 1992 The Atlas of Mouse Development. Academic Press Limited, London., pp 213–227, 252, 265
Losada A, Xia H, Migliazza L, Diez-Pardo JA, Santisteban P, Tovar JA 1999 Lung hypoplasia caused by nitrofen is mediated by down-regulation of the transcription factor TTF-1. Pediatr Surg Int 15: 188–191
Mark M, Rijli FM, Chambon P 1997 Homeobox genes in embryogenesis and pathogenesis. Pediatr Res 42: 421–429
Boulet AM, Capecchi MR 1996 Targeted disruption of hoxc-4 causes esophageal defects and vertebral transformations. Dev Biol 177: 232–249
Litingtung Y, Lei L, Westphal H, Chiang C 1998 Sonic hedgehog is essential to foregut development. Nat Genet 20: 58–61
Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC 1998 Essential function of Gli2 and Gli3 in the formation of lung, trachea, and oesophagus. Nat Genet 20: 54–57
Minoo P, Su G, Drum H, Bringas P, Kimura S 1999 Defects in tracheoesophageal and lung morphogenesis in Nkx 2: 1(-/-) mouse embryos. Dev Biol 209: 60–71
Chisaka O, Capecchi MR 1991 Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox 1: 5. Nature 350: 473–479
Manley NR, Capecchi MR 1995 The role of Hoxa-3 in mouse thymus and thyroid development. Development 121: 1989–2003
Manley NR, Capecchi MR 1997 Hox group 3 paralogous genes act synergistically in the formation of somitic and neural crest-derived structures. Dev Biol 192: 274–288
Manley NR, Capecchi MR 1998 Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands. Dev Biol 195: 1–15
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Supported in part by FIS (Fondo de Investigación Sanitaria, Ministerio de Sanidad y Consumo, Spain) grants #96/0059–01 and #96/1402.
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Otten, C., Migliazza, L., Xia, H. et al. Neural Crest-Derived Defects in Experimental Esophageal Atresia. Pediatr Res 47, 178 (2000). https://doi.org/10.1203/00006450-200002000-00005
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DOI: https://doi.org/10.1203/00006450-200002000-00005
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