Diethylstilbestrol-induced mouse hypospadias: “window of susceptibility”

• Window for DES-induced penile malformations is birth to 15-days postnatal.
• DES-induced penile malformations are reversible in certain treatment groups.
• Mid-shaft DES-induced hypospadias may be impossible in mice.
• Urethral meatal hypospadias is induced by DES treatments during certain periods.

This review presents published and novel results that define the programming window for diethylstilbestrol (DES)-induced abnormal development of the mouse penis. These data indicate that DES has its greatest effect during the period of most intense penile morphogenesis, namely postnatal days 0-15 (P0-P15). Pregnant mice and their neonatal pups were injected subcutaneously with 200ng/gbw DES every other day from embryonic day 12–18 (DES E12–E18), postnatal day 0–10 (DES P0–P10), embryonic day 12 to postnatal day 10 (DES E12–P10), postnatal day 5–15 (DES P5–P15), and postnatal day 10–20 (DES P10–P20). Aged-matched controls received sesame oil vehicle. After euthanasia at 10, 15, 20 and 60 days, penises were analyzed by gross morphology, histology and morphometry. Penises of all 5 groups of DES-treated mice were reduced in size, which was confirmed by morphometric analysis of internal penile structures. The most profound effects were seen in the DES E12–P10, DES P0–P10, and DES P5–P15 groups, thus defining a DES “programming window”. For all parameters, DES treatment from P10 to P20 showed the most mild of effects. Adverse effects of DES on the MUMP cartilage and erectile bodies observed shortly after the last DES injection reverted to normality in the DES P5–P15, but not in the E12–P10 and P0–P10 groups, in which MUMP cartilage and erectile body malformations persisted into adulthood, again emphasizing a “window of susceptibility” in the early neonatal period.