SEX-HORMONES REGULATE CFTR IN DEVELOPING FETAL-RAT LUNG EPITHELIAL-CELLS

Sex hormones modulate two normal processes of late-gestation mammalian lung development the onset of augmented production of surfactant phos pholipids and the loss of mesenchymal cells. As prenatal lung developm ent advances, epithelial chloride secretory pathways diminish as oppos ing sodium absorptive pathways increase in expression. We hypothesized that sex hormones may influence both the gene expression and function al activity of the chloride channel known as the cystic fibrosis trans membrane conductance regulator (CFTR) in fetal lung epithelium. We rep ort here that sex hormones exert opposite effects on CFTR. Androgen in creases and estrogen decreases CFTR functional activity [as assessed b y CFTR antisense (but not sense) oligodeoxynucleotide-sensitive adenos ine 3',5'-cyclic monophosphate-stimulated cell volume reduction or by glibenclamide-sensitive, amiloride-insensitive transepithelial electri cal potential] in primary cultures of fetal rat lung epithelial cells. No alterations in CFTR mRNA levels (measured by quantitative polymera se chain reaction amplification of reverse transcripts) accompanied ei ther the changes in functional activity induced by sex hormones or the changes observed during normal development, suggesting that sex hormo ne modulation of CFTR in antenatal lung occurs at a posttranscriptiona l level. Our data are consistent with the hypothesis that both androge n and estrogen contribute to the male disadvantage with respect to fet al lung functional development.