title: Sex-specific effects of sex steroids on alveolar epithelial Na+transport.
abstract: Alveolar fluid clearance mediates perinatal lung transition to air breathing in newborn infants, which is accomplished by epithelial Na+channels (ENaC) and Na-K-ATPase. Male sex represents a major risk factor for developing respiratory distress, especially in preterm infants. We previously showed that male sex is associated with reduced epithelial Na+transport, possibly contributing to the sexual dimorphism in newborn respiratory distress. This study aimed to determine sex-specific effects of sex steroids on epithelial Na+transport. The effects of testosterone, 5α-dihydrotestosterone (DHT), estradiol, and progesterone on Na+transport and Na+channel expression were determined in fetal distal lung epithelial (FDLE) cells of male and female rat fetuses by Ussing chamber and mRNA expression analyses. DHT showed a minor effect only in male FDLE cells by decreasing epithelial Na+transport. However, flutamide, an androgen receptor antagonist, did not abolish the gender imbalance, and testosterone lacked any effect on Na+transport in male and female FDLE cells. In contrast, estradiol and progesterone increased Na+transport and Na+channel expression especially in females, and prevented the inhibiting effect of DHT in males. Estrogen receptor inhibition decreased Na+channel expression and eliminated the sex differences. In conclusion, female sex steroids stimulate Na+transport especially in females and prevent the inhibitory effect of DHT in males. The ineffectiveness of testosterone suggests that Na+transport is largely unaffected by androgens. Thus, the higher responsiveness of female cells to female sex steroids explains the higher Na+transport activity, possibly leading to a functional advantage in females.
authors.affiliation: Center for Pediatric Research Leipzig, Division of Neonatology, Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Haase
authors.affiliation: Center for Pediatric Research Leipzig, Division of Neonatology, Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany mandy.laube@medizin.uni-leipzig.de.
authors.forename: Mandy
authors.initials: M
authors.lastname: Laube
authors.affiliation: Center for Pediatric Research Leipzig, Division of Neonatology, Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: Thome
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D053503:Epithelial Sodium Channels / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000166:cytology; D005485:Flutamide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000196:embryology; D008297:Male; D021122:Protein Subunits / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D012964:Sodium / Q000378:metabolism*
chemical_list: C556295:4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol; D000728:Androgens; D053503:Epithelial Sodium Channels; D047629:Estrogen Receptor beta; D012739:Gonadal Steroid Hormones; D021122:Protein Subunits; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D005485:Flutamide; D012964:Sodium
keywords: ENaC; epithelial Na+ transport; lung; preterm infants; sex steroids