Essential Intracrine Androgenic Action in Lung Development for Both Sexes

Albeit their recognized negative effects on lung maturation, androgens have been proposed to play an essential positive role in lung development. This work aimed to evaluate the impact of blocking endogenous androgen and estrogen actions and to study the effect of an excess of androgen and estrogen during the end of saccular stage and the beginning of the alveolar stage on lung development. This was performed with normal oxygen atmosphere and with hyperoxia, a model of alveolar simplification, which is observed in new bronchopulmonary dysplasia. Mouse lung samples were collected on postnatal day 9 after exposure to 21% or 80% oxygen (postnatal days 1 to 4), and after administration (postnatal days 3 to 8) of vehicle, pure antiandrogen (flutamide), dihydrotestosterone, pure antiestrogen (fulvestrant), or 17β-estradiol. With 21% oxygen, the major effects on morphometric parameters were induced by flutamide. In contrast, with hyperoxia, both flutamide and dihydrotestosterone had similar effects on several morphometric parameters. For instance, a decrease in the relative frequency of closed areas (mainly composed of saccules/alveoli) < 1000 μm² and an increase for those > 2500 μm² were observed after flutamide administration. In conclusion, during the junction between the saccular and the alveolar stages, endogenous androgens play an essential intracrine role in lung development for both sexes while an excess of androgens are deleterious when combined with a hyperoxia treatment, but not with normal oxygen levels. Endogenous estrogens have no effects on the lungs during the developmental window studied, while exogenous estrogens had only isolated effects on some morphometric parameters.