Lung hypoplasia caused by nitrofen is mediated by down-regulation of thyroid transcription factor TTF-1

Prenatal exposure to nitrofen induces lung hypoplasia and diaphragmatic her nias very similar to those in human disease, but the mechanisms are still u nknown. Thyroid transcription factor 1 (TTF-1) is involved in lung ontogeny and regulation of the expression of surfactant proteins, and is likely abn ormally expressed in nitrofen-induced lung hypoplasia. This study examines the effect of nitrofen on TTF-1 messenger RNA (mRNA) expression in the lung s of prenatal rat fetuses and a human lung-cell line (NCI-H441) that expres ses both TTF-1 and surfactant proteins in vivo. Lungs from preterm fetuses harvested from rats with 100 mg nitrofen an gestational day 9.5 and NCI-H44 1 cells maintained in RPMI medium containing 10% fetal bovine serum and exp osed to nitrofen for different times and concentrations were assayed for TT F-1 mRNA by northern blot analysis. mRNA for TTF-1 was decreased in nitrofe n-exposed pups in comparison with controls, and exposure to nitrofen caused a dose- and time-related decrease in TTF-1 expression in H441 cell culture s. These results indicate that nitrofen down regulates TTF-1 both in vivo a nd in vitro. Since this interferes with lung development, it is reasonable to accept that lung hypoplasia in this model is in part due to the direct e ffect of the teratogen rather than to compression by the abdominal viscera herniated into the thorax. This mechanism should be explored in the clinica l setting.