Androgen Regulation of Signaling Pathways in Late Fetal Mouse Lung Development¹

Abstract

During lung development there is tension between positive and negative regulators of fibroblast-epithelial communication controlling type II cell differentiation. A clinical consequence of imbalance of this tension is the increased risk for respiratory distress syndrome in male infants. We hypothesized that chronic intrauterine androgen exposure alters fetal lung fibroblast maturation by down-regulating epidermal growth factor receptor (EGF-R) activity and by up-regulating transforming growth factor-beta receptor (TGFbeta-R) activity, leading to an inhibition of surfactant protein B (SP-B) and -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 gestational day 11. On day 18, EGF binding, EGF-R phosphorylation, TGFbeta-R binding, and TGFbeta1-induced cell proliferation were studied in sex-specific 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 phosphorylation. TGFbeta-R binding was increased (females to 173+/-39% and males to 280+/-64% of controls), and TGFbeta-induced cell proliferation was increased in female cells (231+/-57% of controls). SP-B and -C messenger RNA expression was reduced to 55+/-10% and 75+/-4%, respectively. We conclude that chronic DHT exposure beginning early in lung development alters the balance of growth factor signaling that regulates lung maturation.

Sex-Specific Differences in MicroRNA Expression During Human Fetal Lung Development

“…Importantly, many of the impacts of sex hormones established from mouse models in later lung development may still apply to earlier lung development. These observations include the finding that androgens alter fetal lung fibroblast maturation in murine lung via EGF and TGF β signaling events ( Dammann et al, 2000 ). Additionally, androgens appear to block endogenous glucocorticoids, which are essential to normal lung development and are promoters of surfactant production ( Provost et al, 2013 ).…”

Increased Risk for Respiratory Complications in Male Extremely Preterm Infants: A Propensity Score Matching Study

“…Increased concentrations of estrogen in female can activate the estrogen beta receptors, upregulate the platelet-derived growth factor alpha and enhance the granulocyte-macrophage colony stimulating factor, thereby promoting lung development and the lung surfactants secretion ( 36 – 38 ). Androgens can inhibit lung maturation and the production of pulmonary surfactant by downregulating epidermal growth factor and upregulating transforming growth factor β1 ( 38 , 39 ).…”

Exposure to second-hand smoke is an independent risk factor of small airway dysfunction in non-smokers with chronic cough: A retrospective case-control study

“…Our data suggest that female gender might be associated with SAD in non-smokers with chronic cough. It has been reported that lung function is influenced by female sex hormones ( 40 ), and androgens affect lung function by inhibiting lung surfactant production in a variety of species through mechanisms that involve altering epidermal growth factor and transforming growth factor-β signaling ( 41 ). However, whether these factors ultimately affect small airway function remains unclear.…”