Abstract
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.
Highlights
Cryptorchidism, hypospadias, low sperm count and testicular germ cell cancer are disorders of male reproductive health that have a high or increasing incidence in the Western world [1,2]
No significant effect on Leydig cell aggregation was observed when animals were exposed to Dex on its own or to di(n-butyl) phthalate (DBP)-500 or DBP-750 when these were administered during the late treatment window (e19.5–e20.5; ie after the masculinization programming window’ (MPW)) (Fig. 3)
Values are Means 6 SEM for 8–15 animals from 3–5 litters per treatment group. ***p,0.001, in comparison with controls; ap,0.001 in comparison with Dex group; bp,0.05 in comparison with DBP-500 late window group; cp,0.001 in comparison with DBP-750 late window group; dp,0.01 in comparison with DBP-750 MPW window group; ep,0.05 in comparison with DBP-750 full treatment window group
Summary
Cryptorchidism, hypospadias, low sperm count and testicular germ cell cancer are disorders of male reproductive health that have a high or increasing incidence in the Western world [1,2] These disorders have been hypothesized to comprise a testicular dysgenesis syndrome (TDS) with a common fetal origin [3,4]. There has been considerable interest in identifying the mechanistic origins of TDS disorders and the events that lead to their development As these fetal events are impossible to study in humans, animal models have been developed, such as in utero exposure of pregnant rats to di(n-butyl) phthalate (DBP), to try and investigate the mechanisms that underlie TDS disorders [5,6,7]. These studies have produced strong supporting evidence for the relationship between somatic cell dysfunction and TDS disorders [8,9,10,11]
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