Nitrofen inhibition of pulmonary growth and development occurs in the early embryonic mouse.
OBJECTIVE
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 +/- 1.9 nitrofen v 13.7 +/- 2.6 control; P <.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 +/- 6.8 nitrofen v 42.9 +/- 8.4 control, P <.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).


CONCLUSIONS
Nitrofen induces primary pulmonary hypoplasia and immaturity in the early embryonic mouse, and this effect persists in culture.
Division of Pediatric Surgery and Developmental Biology Program, Childrens Hospital Los Angeles Research Institute, Los Angeles, CA, USA.
Michael J
MJ
Leinwand
J Denise
JD
Tefft
Jingsong
J
Zhao
Colleen
C
Coleman
Kathryn D
KD
Anderson
David
D
Warburton
D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D015870:Gene Expression; D006548:Hernia, Diaphragmatic / Q000196:embryology; D065630:Hernias, Diaphragmatic, Congenital; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects / Q000196:embryology*; D051379:Mice; D009924:Organ Culture Techniques; D010647:Phenyl Ethers / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism
D015415:Biomarkers; D010647:Phenyl Ethers; D012333:RNA, Messenger; C007350:nitrofen