Lung hypoplasia in the nitrofen model of congenital diaphragmatic hernia occurs early in development.
The teratogen nitrofen produces a congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia in rodent fetuses that closely parallel observations made in humans. We hypothesized that these changes may be due to primary pulmonary hypoplasia and not herniation of the abdominal contents. Timed-pregnant rats were given nitrofen on day 9, and fetuses were harvested on days 13 through 21. Initial evagination of lung buds on gestational day 11 was not delayed in nitrofen-treated fetuses. On gestational day 13, however, there was a significant decrease in the number of terminal end buds in the lungs of nitrofen-exposed fetuses vs. controls. Thymidine-labeled lung epithelial and mesenchymal cells were significantly decreased in nitrofen-treated lungs. Lungs from nitrofen-treated fetuses exhibited wide septae with disorganized, compacted tissue, particularly around the air spaces. Expression of surfactant protein B and C mRNAs was significantly decreased in the nitrofen litters. In situ hybridization of fetal lung tissue at all gestational ages showed no difference in the expression of vascular endothelial growth factor, Flk-1, or Flt-1 mRNAs. Because closure of the diaphragm is completed on gestational day 16 in the rat, our results suggest that lung hypoplasia in this model of CDH is due at least in part to a primary effect of nitrofen on the developing lung.
Guilbert
T W
TW
Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206, USA. guilbert@resep-sci.arizona.edu
Gebb
S A
SA
Shannon
J M
JM
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000473:pathology*; D065630:Hernias, Diaphragmatic, Congenital; D008168:Lung / Q000196:embryology* / Q000473:pathology* / Q000648:ultrastructure; D008222:Lymphokines / Q000235:genetics; D008854:Microscopy, Electron; D010455:Peptides / Q000235:genetics; D010575:Pesticides; D010647:Phenyl Ethers; D011247:Pregnancy; D011498:Protein Precursors / Q000235:genetics; D011510:Proteolipids / Q000235:genetics; D011663:Pulmonary Surfactants / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D016326:Extracellular Matrix Proteins; D008222:Lymphokines; D010455:Peptides; D010575:Pesticides; D010647:Phenyl Ethers; D011498:Protein Precursors; D011510:Proteolipids; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C105511:surfactant protein B propeptide; C077063:Sftpc protein, rat; C501164:Flt1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; C007350:nitrofen