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Androgen Regulation of Signaling Pathways in Late Fetal Mouse Lung Development¹

Department of Pediatrics, Division of Newborn Medicine, Tufts University (C.E.L.D., S.M.R., D.D.M., L.D.P., H.C.N.), Boston, Massachusetts 02111; and Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center (C.E.L.D.), Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Christiane E. L. Dammann, M.D., Department of Pediatrics, Division of Newborn Medicine, Tufts University, Boston, Massachusetts 02111. E-mail: cdammann{at}lifespan.org

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-ß receptor (TGFß-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, TGFß-R binding, and TGFß1-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. TGFß-R binding was increased (females to 173 ± 39% and males to 280 ± 64% of controls), and TGFß-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.

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