Nitrofen‐induced congenital diaphragmatic defects in CD1 mice

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Abstract
In previous clinical reports, we have documented the association of several morphologic changes with congenital diaphragmatic hernia or, perhaps more appropriately termed, congenital diaphragmatic defect (CDD). These anomalies include decreased cardiac mass with left ventricular hypoplasia in infants with left-sided CDDs (Siebert et al., '84), enlarged, asymmetric chests (Siebert and Benjamin, '87), and extrathoracic anomalies (Benjamin et al., '88), including urinary tract anomalies and elevated kidney weights in otherwise normal kidneys (Glick et al., '90; Siebert et al., '90). Hypoplastic lungs and hearts and enlarged chests are thought to result from the herniation of abdominal viscera into the thoracic cavity, but for the renal abnormalities, pathogenesis is unclear. The findings are intriguing, for they could mirror unrecognized developmental relationships between the diaphragm, lung, heart, and kidney. In order to further examine these issues and to test the applicability of experimentally produced CDDs to human disease, we administered nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether), an herbicide known to produce diaphragmatic defects in rodents, to time-mated CD1 mice by gavage feeding on gestational days 8 and 9. Dosages were 200 (low dose) or 500 (high dose) mg/kg body weight, and fetuses were studied on gestational day 18. Diaphragmatic defects occurred in a dose-response fashion: 0% (0/48) control or sham-fed, 5% (5/104) in the low-dose group, and 25% (19/75) in the high-dose group. Several fetuses with cleft palate, renal agenesis, exencephaly/encephalocele, and/or Di-George sequence were noted at the high dose, the latter a previously undescribed finding. Diaphragmatic defects were primarily right sided and only associated with herniation of abdominal viscera in animals exposed to 500 mg/kg. Body weight was uniformly decreased and crown-rump length variably so by nitrofen exposure, while chest diameters were increased. Reduced heart and lung weights and elevated kidney weights were identified in animals exposed to low- or high-dose nitrofen, but this occurred regardless of the presence of a diaphragmatic defect, suggesting that growth of the lung, heart, and kidney is directly affected by nitrofen. Because the effects of nitrofen could not be differentiated from those associated with CDDs or visceral herniation, it is impossible to resolve questions regarding the interrelationships of diaphragmatic defects and pulmonary, renal, and cardiac changes. Morphogenetic, anatomic, and other differences between laboratory rodents and humans reaffirm the need for careful extrapolation between experimental, teratogenic models and human disease.