Meeting Abstract
Hypospadias has increased 200% in the past 40 years, making it the second most common birth defect in the United States. Normal penile development is driven by androgen signaling from the testis, which masculinizes the genitalia through downstream developmental signals. Penis development is tightly controlled by endogenous androgens derived by the testes beginning at embryonic day 13.5. Disruption of androgen dependent signaling during this masculinization window alters penile development and results in mis-localization of the urethra ventrally along the shaft of the penis. Both humans and rodents exhibit a continuous proximal-to-distal range of urethral mis-localization, but the mechanisms that drive this variation are not well known. To begin to understand the drivers of hypospadias severity, we must understand the developmental timeline for initiation of genital masculinization. To determine how dose and timing of androgen signaling antagonism affected hypospadias severity CD1 mice (n=3) were gavaged with a corn oil control, 75, 100, 125 or 150 mg/kg of vinclozolin during two overlapping developmental windows (E 13.5-16.5 and E 14.5-16.5). On E18.5 pups were sacrificed and urethral length was evaluated histologically. We find that E 13.5 is an important day for genital masculinization, and that exposing individuals to vinclozolin during this embryonic time point leads to a shorter urethral length and alters genital masculinization across the dose response. We identify a dose and time window that future studies analyzing developmental and molecular mechanisms driving hypospadias can use to induce consistent variation in hypospadias severity.
