Abstract
Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal ‘masculinization programming window’. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ∼3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3β-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.
Highlights
Phenotypic masculinization is a pivotal event in mammalian development, diverting the fetus from the female ‘set-up’ programme of development
To characterize the relationship between COUP-TFII and steroidogenesis, we initially utilized an established dibutyl phthalate (DBP) treatment regime (500 mg/kg/day from e13.5–e21.5) that induces a major reduction in intratesticular testosterone (ITT) at e21.5, leading to a high incidence of testicular dysgenesis syndrome (TDS)-like disorders in adulthood (Fig. 1B)
The present study has identified a novel mechanism that could potentially play a key role in up-regulating testosterone production by rat fetal Leydig cells (LC) during and after the critical masculinization programming window (MPW) [1,2]
Summary
Phenotypic masculinization is a pivotal event in mammalian development, diverting the fetus from the female ‘set-up’ programme of development. The key driver of this process is testosterone produced by the fetal Leydig cells (LC) [1] This occurs early in fetal development, immediately after testis differentiation, in what has been termed the masculinization programming window (MPW; e15.5–e18.5 in the rat) [1,2]. Regulation of testosterone production by fetal LC within and after the MPW is fundamentally important for normal male development, yet the mechanisms involved are largely unknown (Fig. 1A). In humans/primates, inactivating mutations of the LH receptor, not of LH, impair masculinization [1] This is because the primate placenta produces an LH-like chorionic gonadotropin (CG) that stimulates fetal LC, whereas the rodent placenta does not [1]. Ignorance about the regulation of fetal testis steroidogenesis in and around the MPW is a major obstacle to identifying how normal masculinization is driven and what can impact this to induce TDS/masculinization disorders
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