The testicular dysgenesis syndrome (TDS) hypothesis, which proposes that common reproductive disorders of newborn and adult human males may have a common fetal origin, is largely untested. We tested this hypothesis using a rat model involving gestational exposure to dibutyl phthalate (DBP), which suppresses testosterone production by the fetal testis. We evaluated if induction of TDS via testosterone suppression is restricted to the “masculinization programming window” (MPW), as indicated by reduction in anogenital distance (AGD). We show that DBP suppresses fetal testosterone equally during and after the MPW, but only DBP exposure in the MPW causes reduced AGD, focal testicular dysgenesis, and TDS disorders (cryptorchidism, hypospadias, reduced adult testis size, and compensated adult Leydig cell failure). Focal testicular dysgenesis, reduced size of adult male reproductive organs, and TDS disorders and their severity were all strongly associated with reduced AGD. We related our findings to human TDS cases by demonstrating similar focal dysgenetic changes in testes of men with preinvasive germ cell neoplasia (GCNIS) and in testes of DBP-MPW animals. If our results are translatable to humans, they suggest that identification of potential causes of human TDS disorders should focus on exposures during a human MPW equivalent, especially if negatively associated with offspring AGD.
Sander van den Driesche, Karen R. Kilcoyne, Ida Wagner, Diane Rebourcet, Ashley Boyle, Rod Mitchell, Chris McKinnell, Sheila Macpherson, Roland Donat, Chitranjan J. Shukla, Anne Jorgensen, Ewa Rajpert-De Meyts, Niels E. Skakkebaek, Richard M. Sharpe
Effect of fetal exposure of rats to dibutyl phthalate during the masculinization programming window or immediately afterward (late window) on intratesticular testosterone, anogenital distance, and gross testis morphology at E17.5 and E21.5. Intratesticular testosterone (A), anogenital distance (B), and gross testis morphology (C–G) at E17.5 and E21.5. Note that E17.5 is during the MPW, E21.5 is at the end of the LW.