Nitrofen inhibition of pulmonary growth and development occurs in the early embryonic mouse

Background/Purpose: It was believed previously that pulmonary hypoplasia in congenital diaphragmatic hernia (CDH) was a consequence of the herniation of abdominal viscera into the chest. Using the murine nitrofen-induced model of CDH, the authors evaluated lung growth and development before diaphragm closure or herniation. Methods: The authors examined nitrofen-exposed early embryonic lungs on embryonic day 12 (E12). Branching morphogenesis was quantified before and after 4 days in culture in serumless chemically defined media and compared with age-matched control lungs. The mRNA expression of proliferative and developmental markers in cultured lungs was then determined. Results: Nitrofen-exposed lungs had 30% fewer total terminal branches than age-matched controls (9.3 [plusmn] 1.9 nitrofen v 13.7 [plusmn] 2.6 control; P [lt ] .001). Hypoplasia also was more profound in the left than the right lung. These effects persisted after culturing the lungs for 4 days in serumless chemically-defined media (31.7 [plusmn] 6.8 nitrofen v 42.9 [plusmn] 8.4 control, P [lt ] .001). Furthermore, the mRNA expression of proliferative and developmental markers was decreased in nitrofen-exposed E12 lungs cultured for 4 days (as a percentage of age-matched controls): cyclin A (69.28%; P = .04), Nkx2.1 (44.4%, 0.04), SP-A (24.1%; P = .008), SP-B (23.4%; P = .05), SP-C (20%; P = .06), and CC-10 (13.8%; P = .04). Conclusion: Nitrofen induces primary pulmonary hypoplasia and immaturity in the early embryonic mouse, and this effect persists in culture. J Pediatr Surg 37:1263-1268.