Abstract
Administration of dibutyl phthalate (DBP) to pregnant rats causes reproductive disorders in male offspring, resulting from suppression of intratesticular testosterone, and is used as a model for human testicular dysgenesis syndrome (TDS). DBP exposure in pregnancy induces focal dysgenetic areas in fetal testes that appear between e19.5–e21.5, manifesting as focal aggregation of Leydig cells and ectopic Sertoli cells (SC). Our aim was to identify the origins of the ectopic SC. Time-mated female rats were administered 750 mg/kg/day DBP in three different time windows: full window (FW; e13.5–e20.5), masculinisation programming window (MPW; e15.5–e18.5), late window (LW; e19.5–e20.5). We show that DBP-MPW treatment produces more extensive and severe dysgenetic areas, with more ectopic SC and germ cells (GC) than DBP-FW treatment; DBP-LW induces no dysgenesis. Our findings demonstrate that ectopic SC do not differentiate de novo, but result from rupture of normally formed seminiferous cords beyond e20.5. The more severe testis dysgenesis in DBP-MPW animals may result from the presence of basally migrating GC and a weakened basal lamina, whereas GC migration was minimal in DBP-FW animals. Our findings provide the first evidence for how testicular dysgenesis can result after normal testis differentiation/development and may be relevant to understanding TDS in human patients.
Highlights
Administration of dibutyl phthalate (DBP) to pregnant rats causes reproductive disorders in male offspring, resulting from suppression of intratesticular testosterone, and is used as a model for human testicular dysgenesis syndrome (TDS)
DBP-masculinisation programming window (MPW) and DBP-full window (FW) groups both showed the appearance of focal dysgenetic areas at e21.5, in which ectopic Sertoli (SOX9+) and germ (VASA+) cells were evident in the interstitial compartment (Fig. 1b,c,e,f)
The present findings, in an established rat model for TDS12, 13, 23, 37, add a new dimension to this thinking, as they demonstrate that induction of focal dysgenesis in the rat testis, which is intimately associated with occurrence of later TDS disorders[12, 15,16,17, 33], is induced after normal testis cell differentiation and organisation have occurred
Summary
Administration of dibutyl phthalate (DBP) to pregnant rats causes reproductive disorders in male offspring, resulting from suppression of intratesticular testosterone, and is used as a model for human testicular dysgenesis syndrome (TDS). DBP exposure suppresses intratesticular testosterone in fetal males, resulting in TDS disorders[11, 15], which are often accompanied by areas of focal dysgenesis in the testis, manifesting as malformed seminiferous tubules and abnormal distribution of somatic cells in these focal areas (e.g. intratubular Leydig cells)[12, 16, 17]. The latter events occur normally in DBP-exposed fetuses[18, 24], but even when DBP exposure is initiated after cord formation (e15.5), ectopic Sertoli cells still appear later in gestation Because of these observations, we have reasoned that either the ectopic Sertoli cells result from de novo differentiation between e19.5–e21.5 or they derive from the breakdown of already formed seminiferous cords. After cord formation, the fetal Leydig cells differentiate and begin to produce insulin-like factor 3 and testosterone which, together with anti-müllerian hormone produced by the Sertoli cells, are responsible for masculinising the internal and external genitalia[8, 11]
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