Y It Matters—Sex Differences in Fetal Lung Development (original) (raw)
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Sex Differences in Fetal Rabbit Pulmonary Surfactant Production
Pediatric Research, 1981
New Zealand White rabbit does were mated between 0900 and than females at concurrent gestations. Recent evidence in humans 1200 hr and sacrificed between these hours on day 24, 26, 28, or has linked fetal sex with differences in amniotic fluid indices of 30 of gestation (day 0 = day of mating; term = 31 days). Does lung maturation. We tested the hypothesis that the late gestation were sacrificed with an intravenous injection of pentobarbital (180 surge in pulmonary surfactant production occurs later in the male mg). The uterus was then exposed, and the fetuses were sacrificed fetus than in the female fetus in the rabbit model. We measured with 30 mg of pentobarbital intraperitoneally, injected through saturated phosphatidylcholine and total phosphatidylcholine in the uterine wall. AF was obtained on each fetus by puncturing the lung lavage a t 26, 28, and 30 days gestation and in amniotic fluid fetal membranes after dissecting away the uterine wall. Each fetus a t 24,26,28, and 30 days gestation (term = 31 days). The saturated was weighed and then tracheostomized, and LL was obtained by phosphatidylcholine/sphingomyelin ratios were 158 and 55% lavaging the lungs with 5 X 0.5 ml of 0.9% iced NaCl solution. We higher in female fetal lung lavage a t 26 and 28 days, respectively, were unable to obtain reliable LL samples on 24 day gestation and 75% higher in amniotic fluid at 28 days (P < 0.05). The total fetuses. Bloody LL or AF samples were discarded. Fetal sex was phosphatidylcholine/sphingomyelin ratios were 39% higher in fe-determined by inspection of the gonads and confirmed histologimale fetal lung lavage and 35% higher in female amniotic fluid a t cally.
Sex-specific effects of sex steroids on alveolar epithelial Na+ transport
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2017
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...
Early Human Development, 2009
Background: Vascular endothelial growth factor (VEGF) is essential for embryonic lung development and has been shown to be regulated by estradiol (E2) and progesterone (P). Aim: To investigate the effects of prenatal E2 and P withdrawal by specific receptor antagonists on the mRNA expression of VEGF, surfactant proteins (SP-B and SP-C) and on alveolarisation in lung tissue of male and female pig fetuses. Methods: Fetuses from 10 sows were randomized to receive either both an intramuscular injection of the E2 receptor blocker ICI 182.780 and the P receptor blocker RTI 3021-022 (ICI + RTI, n = 5) or a placebo injection (n = 5) at 90 days of gestation (DOG, 115 = term). After delivery by cesarean section on 114 DOG, tissue of the left lingula of the piglet's lung (28 placebo, 26 ICI + RTI) was obtained to determine the mRNA expression of VEGF, SP-B and SP-C. Lungs from 15 placebo and 14 ICI + RTI group piglets were removed and alveolar counts performed. Results: The ICI + RTI group showed significantly lower SP-C mRNA expression and alveolar counts compared to the placebo group (p = 0.04 and 0.03, respectively). Diminished alveolarisation in the ICI + RTI group was mainly due to the reduction of alveolar counts in male piglets (p = 0.02). Within the placebo group VEGF and SP-B mRNA expression in male piglets were significantly lower compared to female piglets (p = 0.01 and 0.004, respectively). ICI + RTI treatment abolished this gender-related difference. Conclusion: Estradiol and P antagonism affected gender-related differences of key proteins for pulmonary function and development and especially in males was associated with diminished alveolarisation.
Gene expression profile of androgen modulated genes in the murine fetal developing lung
Reproductive Biology and Endocrinology, 2010
Background Accumulating evidences suggest that sex affects lung development. Indeed, a higher incidence of respiratory distress syndrome is observed in male compared to female preterm neonates at comparable developmental stage and experimental studies demonstrated an androgen-related delay in male lung maturation. However, the precise mechanisms underlying these deleterious effects of androgens in lung maturation are only partially understood. Methods To build up a better understanding of the effect of androgens on lung development, we analyzed by microarrays the expression of genes showing a sexual difference and those modulated by androgens. Lungs of murine fetuses resulting from a timely mating window of 1 hour were studied at gestational day 17 (GD17) and GD18, corresponding to the period of surge of surfactant production. Using injections of the antiandrogen flutamide to pregnant mice, we hunted for genes in fetal lungs which are transcriptionally modulated by androgens. Result...
Journal of Clinical Investigation, 1985
A sexual dimorphism in fetal pulmonary maturation has been described in which the female fetal lung produces surfactant earlier in gestation than the male fetal lung. This is felt to be related to the increased incidence in male newborns of the Respiratory Distress Syndrome. Dihydrotestosterone will delay surfactant production in the female fetus, and a relationship between fetal sexual differentiation and fetal lung maturation has been proposed. We hypothesized that the dimorphism in fetal surfactant production is dependent on androgen receptor function. We measured phosphatidylcholine (PC), saturated phosphatidylcholine (SPC), and sphingomyelin (S) in the amniotic fluid of fetal mice of the mouse model of testicular feminization (Tfm mouse). In this model, male carriers of the X-linked Tfm gene have no functional androgen receptors. The mean amniotic fluid phosphatidylcholine to sphingomyelin ratio (PC/S ratio) was 28% higher in females than in normal males, and the amniotic fluid PC/S ratio of the Tfm male fetuses was the same as the females. The ratio of amniotic fluid saturated phosphatidylcholine to sphingomyelin (SPC/S ratio) was lowest in males, intermediate in females, and highest in Tfm males. A significant relationship between the fetal groups and the amniotic fluid SPC/S ratio was identified by analysis of variance. There were no differences in the whole lung phospholipid content between the three groups.
Gender Differences in Respiratory Morbidity and Mortality of Preterm Neonates
Frontiers in Pediatrics, 2017
For the past century, researchers have underscored the "disadvantage" observed in respiratory morbidity and mortality of male newborns. In this contemporary review, we examine gender differences in preterm infant respiratory morbidity and mortality specifically appraising differences in the very low birth weight (VLBW) population as well as the late preterm (LPT) population. In the era of postnatal surfactant and antenatal corticosteroids, the gender gap in neonatal outcomes has not narrowed. Structural, physiologic, and hormonal sex differences may be at the root of this disparity. Further exploration into the origin of gender differences in respiratory morbidity and neonatal mortality will shape future therapies. These therapies may need to be gender specific to close the gender gap.
Cummings, James J. Nitric oxide decreases lung liquid production in fetal lambs. J. Appl. Physiol. 83(5): 1538-1544, 1997.-To examine the effect of nitric oxide on fetal lung liquid production, I measured lung liquid production in fetal sheep at 130 Ϯ 5 days gestation (range 122-137 days) before and after intrapulmonary instillation of nitric oxide. Thirtyone studies were done in which net lung luminal liquid production (Jv) was measured by plotting the change in lung luminal liquid concentration of radiolabeled albumin, an impermeant tracer that was mixed into the lung liquid at the start of each study. To see whether changes in Jv might be associated with changes in pulmonary hemodynamics, pulmonary and systemic pressures were measured and left pulmonary arterial flow was measured by an ultrasonic Doppler flow probe. Variables were measured during a 1-to 2-h control period and for 4 h after a small bolus of isotonic saline saturated with nitric oxide gas (10 or 100%) was instilled into the lung liquid. Control (saline) instillations (n ϭ 6) caused no change in any variable over 6 h. Nitric oxide instillation significantly decreased Jv and increased pulmonary blood flow; these effects were sustained for 1-2 h. There was also a significant but transient decrease in pulmonary arterial pressure. Thus intrapulmonary nitric oxide causes a significant decrease in lung liquid and is associated with a decrease in pulmonary vascular resistance. In a separate series of experiments either amiloride or benzamil, which blocks Na ϩ transport, was mixed into the lung liquid before nitric oxide instillation; still, there was a similar reduction in lung liquid production. Thus the reduction in lung liquid secretion caused by nitric oxide does not appear to depend on apical Na ϩ efflux. pulmonary circulation; ion transport; birth transition; fetus
Scientific Reports, 2021
Male sex remains an independent risk factor for respiratory distress syndrome (RDS) in preterm infants. Insufficient Na + transport-mediated alveolar fluid clearance contributes to RDS development and we previously demonstrated sex-specific differences in Na + transport. The epidermal growth factor (EGF) is important during fetal lung development with possible influence on Na + transport. Sex-specific effects of EGF during surfactant synthesis were shown. We thus determined whether EGF exerts sex-specific effects on Na + transport in fetal alveolar cells. We analyzed sex-specific fetal distal lung epithelial (FDLE) cells exposed to EGF and related ligands with Ussing chambers, RT-qPCR and Western blots. EGF strongly reduced the epithelial Na + channel (ENaC) mRNA levels in both male and female FDLE cells. This was corroborated by a markedly reduced ENaC activity, while amiloride-insensitive pathways as well as barrier function were raised by EGF. In contrast to chronic effects, acute effects of EGF were sex-specific, because Na + transport was reduced only in males. AKT phosphorylation was elevated only in female cells, while pERK1/2 was increased in both male and female cells. EGF showed certain sex-and time-dependent effects in FDLE cells. Nevertheless, the results suggest that EGF is an unlikely cause for the sex-specific differences in Na + transport. During fetal development, lung epithelial cells actively secrete fluid, thereby filling the developing lung. Vectorial Cl − transport-driven pulmonary fluid accumulation supports lung growth by establishing an intra-pulmonary pressure that promotes cellular proliferation. Animal studies with intrauterine tracheal drainage as well as tracheal occlusion demonstrated the pivotal relationship between fluid accumulation and fetal lung development 1. A contribution of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) to this process has been suggested 2-4. More precisely, during fetal lung development CFTR expression exhibits a time-and tissuedependent expression pattern. The highest CFTR expression level was observed in the 1st and 2nd gestational trimester, while its expression gradually declines during the 3rd trimester 5,6. Epithelial cell proliferation was accelerated by Cftr over-expression in the pseudoglandular stage resulting in an enhanced lung growth 3. Prior to birth, the fetal lung fluid has to be removed to enable air breathing. Alveolar fluid clearance (AFC) is driven by epithelial Na + transport accomplished by epithelial Na + channels (ENaC) in the apical membrane compartment and the Na,K-ATPase in the basolateral membrane compartment of alveolar type II (ATII) cells. ENaC consist of three homologous subunits, α-, β-, and γ-ENaC 7 , and the Na-K-ATPase is composed of α 1-and β 1-subunits in ATII cells 8. Vectorial Na + transport establishes an osmotic driving force causing fluid absorption from the air spaces into the interstitium. In premature newborns a decreased AFC has been shown 9 , possibly due to a lower expression of epithelial Na + channels 10. In addition to surfactant deficiency, AFC insufficiency contributes to the development of the respiratory distress syndrome (RDS) 10. Importantly, a sex ratio of 1:1.7 11,12 was observed for the RDS incidence, with males developing RDS significantly more frequently compared with female infants of the same gestational age, raising male mortality 13. Up until now, male sex remains an independent risk factor for RDS development 11,12. We have previously shown sex-specific differences in alveolar Na + transport. Male sex was associated with lower Na + transport and reduced levels of the ENaC and Na-K-ATPase subunits in fetal distal lung epithelial (FDLE) cells 14. Na + transport in female cells was more responsive to female sex steroids