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Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window.

ABSTRACT: 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.

SUBMITTER: van den Driesche S

PROVIDER: S-EPMC5358493 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window.

van den Driesche Sander S Kilcoyne Karen R KR Wagner Ida I Rebourcet Diane D Boyle Ashley A Mitchell Rod R McKinnell Chris C Macpherson Sheila S Donat Roland R Shukla Chitranjan J CJ Jorgensen Anne A Meyts Ewa Rajpert-De ER Skakkebaek Niels E NE Sharpe Richard M RM

JCI insight 20170323 6

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 red ...[more]

PMID: 28352662

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Project description:The testicular dysgenesis syndrome (TDS) hypothesis proposes that maldevelopment of the testis, irrespective of cause, leads to malfunction of the somatic (Leydig, Sertoli) cells and consequent downstream TDS disorders. Studies in rats exposed in utero to di(n-butyl) phthalate (DBP) have strongly supported the TDS concept, but so far no direct evidence has been produced that links dysgenesis per se to somatic cell dysfunction, in particular to androgen production/action during the 'masculinization programming window' (MPW; e15.5-e18.5). Normal reproductive tract development and anogenital distance (AGD) are programmed within the MPW, and TDS disorders arise because of deficiencies in this programming. However, DBP-induced focal testicular dysgenesis (Leydig cell aggregation, ectopic Sertoli cells, malformed seminiferous cords) is not evident until after the MPW. Therefore, we used AGD as a read-out of androgen exposure in the MPW, and investigated if this measure was related to objectively quantified dysgenesis (Leydig cell aggregation) at e21.5 in male fetuses exposed to vehicle, DBP (500 or 750 mg/kg/day) or the synthetic glucocorticoid dexamethasone (Dex; alone or plus DBP-500) from e15.5-e18.5 (MPW), e13.5-e20.5 or e19.5-e20.5 (late window). Dysgenesis was found only in animals exposed to DBP during the MPW, and was negatively correlated (R² = -0.5) with AGD at e21.5 and at postnatal day 8, irrespective of treatment period. Dysgenesis was also negatively correlated (R² = -0.5) with intratesticular testosterone (ITT) at e21.5, but only when treatments in short windows (MPW, late window) were excluded; the same was true for correlation between AGD and ITT. We conclude that AGD, reflecting Leydig cell function solely within the MPW, is strongly related to focal dysgenesis. Our results point to this occurring because of a common early mechanism, targeted by DBP that determines both dysgenesis and early (during the MPW) fetal Leydig cell dysfunction. The findings provide strong validation of the TDS hypothesis.

Dataset Information

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window.

Publications

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window.

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