Androgen regulation of signaling pathways in late fetal mouse lung development

During lung development there is tension between positive and negative regu lators of fibroblast-epithelial communication controlling type II cell diff erentiation. A clinical consequence of imbalance of this tension is the inc reased risk for respiratory distress syndrome in male infants. We hypothesi zed that chronic intrauterine androgen exposure alters fetal lung fibroblas t maturation by down-regulating epidermal growth factor receptor (EGF-R) ac tivity and by up-regulating transforming growth factor-beta receptor (TGF b eta-R) activity, leading to an inhibition of surfactant protein B (SP-B) an d -C (SP-C) gene expression in type II cells. We treated pregnant mice with dihydrotestosterone (DHT; 2 mg/day) or vehicle for 7 days, starting on ges tational day 11. On day 18, EGF binding, EGF-R phosphorylation, TGF beta-R binding, and TGF beta 1-induced cell proliferation were studied in sex-spec ific fibroblast cultures. SP-B and -C messenger RNA levels were measured in whole lungs. Chronic DHT treatment reduced both EGF binding (females to 78 +/- 8% and males to 65 +/- 9% of controls) and EGF-induced EGF-R phosphory lation. TGF beta-R binding was increased (females to 173 +/- 39% and males to 280 +/- 64% of controls), and TGF beta-induced cell proliferation was in creased in female cells (231 +/- 57% ofcontrols). SP-B and -C messenger RNA expression was reduced to 55 +/- 10% and 75 +/- 4%, respectively. We concl ude that chronic DHT exposure beginning early in lung development alters th e balance of growth factor signaling that regulates lung maturation.