Subtle morphological and molecular responses to low-dose diethylstilbestrol in the developing rat penis

Developmental exposure to estrogenic chemicals can cause hypospadias in mice. In rats and humans this link is less well-defined, and the causal relationship remains unclear. This likely pertains to uncertainties regarding direct and indirect effects of estrogens in the genital tubercle (GT) and inconsistent evaluations of potentially mild disruptions, especially in rats. In this study, we investigated the effects of late gestational exposure to the estrogenic chemical diethylstilbestrol (DES) in low doses on male rat penis differentiation. In an ex vivo GT culture system, DES caused subtle changes to GT morphology after 96 h in culture, but with no overt phenotype. Moreover, DES upregulated Ar and AR-responsive genes in the GT. When exposing rats in vivo from gestational day (GD) 7-21, DES did not cause genital malformations in the fetal males, but we observed slight abnormalities to GT morphology in µCT scans. Our study indicates that DES may directly modulate hormone signaling in the GT during fetal masculinization.