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.
Leinwand
Michael J
MJ
Division of Pediatric Surgery and Developmental Biology Program, Childrens Hospital Los Angeles Research Institute, Los Angeles, CA, USA.
Tefft
J Denise
JD
Zhao
Jingsong
J
Coleman
Colleen
C
Anderson
Kathryn D
KD
Warburton
David
D
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