In utero prednisone exposure affects genital development

The etiology of the worldwide incidence of hypospadias remains unexplained. Data from the Center for Disease Control suggest that maternal asthma exposure may be a risk factor. The development of the mouse and human urethra shows significant similarities, such as fusion of 2 epithelial edges, closure of a midline epithelial seam and subsequent cellular remodeling, to justify the use of the mouse as an experimental animal model. Prednisone may act as a weak androgen directly or alternatively lowering testosterone by hypothalamic suppression of gonadotropins. We describe the effects of prednisone on urethral formation in the mouse.

The model comprised 10, 20 and 20 timed pregnant C57/6 mice exposed to 1,000, 200 and 100 mg/kg prednisone, respectively, on gestational days 12 through 18. The morphology of the genital tubercles of both sexes were examined on gestational day 19 using histological techniques and 3-dimensional computer reconstruction. Specific attention was focused on the developing urethral seam.

Microscopic serial analysis confirmed the presence of an arrest in seam formation in approximately 25% of male fetuses given supraphysiological doses of prednisone (1,000 mg/kg). In contrast, acceleration of urethral fold fusion and a longer urethral tube were observed in those males treated with 100 and 200 mg/kg prednisone. The female fetuses treated with the same dosages of prednisone did not show any change at the level of the urethral seam area or in the remainder of the genital tubercles.

Supraphysiological doses of prednisone treatment has an inhibitory effect on urethral fold fusion leading to hypospadias whereas low doses accentuate urethra formation in male mouse fetuses. In mice lower doses do not cause hypospadias in the males or affect urethral formation in females.