Original ArticleEarly development of the primordial mammalian diaphragm and cellular mechanisms of nitrofen-induced congenital diaphragmatic hernia |
| Robin D. Clugston, Wei Zhang, John J. Greer * |
Department of Physiology, University of Alberta, Edmonton, Canada
|
| email: John J. Greer (John.greer@ualberta.ca) |
*Correspondence to John J. Greer, Department of Physiology, University of Alberta, 524 HMRC, Edmonton, Alberta, Canada, T6G 2S2
Funded by:
Canadian Institutes of Health Research
March of Dimes
Alberta Heritage Foundation for Medical Research
| cell proliferation • congenital diaphragmatic hernia • human • nitrofen • pleuro-peritoneal fold |
| Congenital diaphragmatic hernia (CDH) is a frequently occurring cause of neonatal respiratory distress and is associated with high mortality and long-term morbidity. Evidence from animal models suggests that CDH has its origins in the malformation of the pleuroperitoneal fold (PPF), a key structure in embryonic diaphragm formation. The aims of this study were to characterize the embryogenesis of the PPF in rats and humans, and to determine the potential mechanism that leads to abnormal PPF development in the nitrofen model of CDH. Analysis of rat embryos, and archived human embryo sections, allowed the timeframe of PPF formation to be determined for both species, thus delineating a critical period of diaphragm development in relation to CDH. Experiments on nitrofen-exposed NIH 3T3 cells in vitro led us to hypothesize that nitrofen might cause diaphragmatic hernia in vivo by two possible mechanisms: through decreased cell proliferation or by inducing apoptosis. Data from nitrofen-exposed rat embryos indicates that the primary mechanism of nitrofen teratogenesis in the PPF is through decreased cell proliferation. This study provides novel insight into the embryogenesis of the PPF in rats and humans, and it indicates that impaired cell proliferation might contribute to abnormal diaphragm development in the nitrofen model of CDH. Birth Defects Research (Part A) 2010. © 2009 Wiley-Liss, Inc. |
Received: 27 April 2009; Revised: 7 June 2009; Accepted: 8 June 2009
10.1002/bdra.20613
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