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Male fetuses exhibit delayed lung maturation and surfactant production in comparison with female fetuses. This delay may be related to sex hormone effects: estrogen enhances and androgens delay lung development. The uptake of glucose, an important precursor for surfactant synthesis, may be differently affected by estrogen and androgens. In these studies we determined the effects of these two hormones on glucose transport (glucose uptake, glucose transporter [Glut] 1 protein, and mRNA) and hexokinase activity in lung tissue of fetal rats. On Day 20 of gestation (term = 21.5 d) lung tissue was harvested from female and male fetal rats, minced into explants, and cultured for 24 h. Basal glucose uptake, measured in the absence of sex hormones, was 37% higher (P < 0.05) in female compared with male lungs. Explants were washed and cultured for an additional 3 h or 24 h in either estradiol or dihydrotestosterone (DHT) at 0, 1, 10, or 100 nM. Twenty-four-hour treatment with estradiol in both male and female explants increase 2-deoxyglucose uptake, Glut 1 protein, and mRNA levels (P < 0.05). However, explants from male fetuses were not as responsive to estradiol treatment as were those from females (P < 0.05). Treatment for 24 h with DHT decreased 2-deoxyglucose uptake, Glut 1 protein, and mRNA levels in females and males (P < 0.05). There was no difference in response between females and males. Short-term incubation (3 h) with sex hormones had no effect on glucose uptake. However, 3-h treatment with estradiol did increase Glut 1 mRNA levels (P < 0.05). Hexokinase activity was not affected by estradiol or DHT treatment. These findings indicate that estradiol and DHT differentially regulate glucose uptake in fetal rat lung tissue. This regulation of substrate supply (glucose) by estradiol and DHT may be another mechanism for the sexual dimorphism observed in lung development and surfactant synthesis.