Meeting Abstract
Hypospadias occurs when the urethra exits ventrally along the penis, rather than the distal tip. Hypospadias is second most common birth defect in the US and exposure to endocrine disrupting chemicals is strongly associated with hypospadias incidence. Normal penis development is tightly controlled by endogenous androgens produced by the testes. Disruption of androgen dependent signaling during this masculinization window alters several aspects of penile development and results in feminization of the penis. Both humans and rodents exhibit a continuous range of hypospadias severity, 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. Previously studies document E13.5 androgen signaling to be non-essential for proper penis development. To determine how dose and timing of androgen signaling antagonism affects hypospadias severity CD1 mice were separated into 2 dosing groups. Mice exposed an earlier dosing window received corn oil control (CO), 75, 100, 125, and 150 mg/kg of vinclozolin on embryonic days (E) 13.5-16.5. Mice exposed to the later dosing window received the same doses on E14.5-16.5. To test if effects were due to the timing of exposure or total dose we also dosed with 200 mg/kg for the four-day window. This design allows us to evaluate the importance of anti-androgen exposure timing versus the total amount of antiandrogen exposure for altering hypospadias severity. We find that blocking androgen when at the time it is produced increases the potency of the androgen antagonist. This suggests that E 13.5 is a critical day that primes the genitalia to respond to testosterone signaling later in development.
