Androgens delay human fetal lung maturation in vitro.
The mature lung produces pulmonary surfactant, a lipid-protein complex that prevents lung alveoli from becoming atelectatic. The prenatal surge of surfactant production in preparation for birth occurs between 28-34 weeks gestation and is triggered by glucocorticoids, which stimulate surfactant synthesis by alveolar epithelial cells through a series of biochemical steps mediated by mesenchymal-epithelial interactions. In contrast to this, when explanted midgestation human fetal lung tissue is maintained in serum-free medium, there is a spontaneous increase (40%) in de novo saturated phosphatidylcholine (SPC) synthesis on the fifth day in culture. Addition of dexamethasone (DEX; 1 x 10(-8) M) to the culture medium causes the increased synthesis in SPC to occur earlier (day 4) and to a greater extent (87%). Addition of an equimolar concentration of dihydrotestosterone (DHT) to the medium delays both the spontaneous and DEX-stimulated increases in SPC synthesis by 24 h. Weak fetal adrenal androgens are also able to block both spontaneous and DEX-stimulated SPC synthesis. Addition of DHT to the explant cultures at daily intervals reveals that inhibition of the DEX effect occurs within the first 24 h after exposure. The antiandrogen flutamide neutralizes the effect of DHT, indicating that it acts through the androgen receptor to block the glucocorticoid. Therefore, the human fetal adrenal cortex may time lung development through both inhibitory and stimulatory mechanisms.
Torday
J S
JS
Department of Pediatrics (Physiology), Harvard Medical School, Boston, Massachusetts 02115.
D000728:Androgens / Q000008:administration & dosage / Q000494:pharmacology*; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000494:pharmacology; D005325:Fetal Organ Maturity / Q000187:drug effects; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000096:biosynthesis; D011663:Pulmonary Surfactants / Q000096:biosynthesis
D000728:Androgens; D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D013196:Dihydrotestosterone; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D005485:Flutamide; D003907:Dexamethasone