SEMINAR: Use of animal models to gain novel insights into human masculinisation disorders

The Seminar: The ‘testicular dysgenesis syndrome’ (TDS) hypothesis proposes that maldevelopment of the testis, which could have numerous primary causes, leads secondarily to malfunction of the Leydig cell (LC) and/or Sertoli (SC) cells and consequent downstream disorders. For example, fetal LC dysfunction can lead to human male reproductive disorders that manifest at birth (cryptorchidism, hypospadias) or in young adulthood (low sperm count, testicular germ cell cancer, lower testosterone levels). The factors regulating fetal somatic cell function in early gestation are unknown, but can be disrupted experimentally in rats by environmental chemicals (eg dibutyl phthalate (DBP)). Gestational exposure to DBP also causes a reduction in fetal germ cell (GC) number, GC aggregation and multinucleated GC. Normal reproductive tract development and anogenital distance (AGD) are programmed within the ‘masculinisation programming window’ (MPW, e15.5-e18.5 in rats; ~8-14 weeks of gestation in humans), and TDS disorders appear to arise because of deficiencies in this programming. We have identified a novel repressor mechanism that explains this vulnerability, which may represent a mechanism underpinning TDS disorders. In rats, intratesticular testosterone (ITT) and fetal LC size increase ~3-fold between e15.5-e21.5, associated with a progressive decrease in LC nuclear expression of Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII), which competes for binding sites in gene promoters with steroidogenic factor 1 (SF-1). Reductions in fetal ITT in rats induced by DBP, diethylstilbestrol or dexamethasone are all associated with maintenance/induced LC nuclear expression of COUP-TFII. We have also explored the species-specificity of COUP-TFII repression of LC steroidogenesis and whether this might determine species-specificity in potential vulnerability to disruption by environmental chemicals/endogenous hormones. Thus in mice, DBP exposure fails to prolong the expression of COUP-TFII in fetal LC, consistent with the absence of DBP-induced suppression of steroidogenesis in this species. In humans, COUP-TFII expression in fetal LC declines from 1st to 2nd trimester, consistent with a potential role in expansion of LC steroidogenic capacity, as in rats. However, our preliminary studies using human fetal testis xenografts into mice treated with DBP, show no evidence for inhibition of LC steroidogenesis and no prolongation/induction of COUP-TFII in fetal LC. We propose that relief of COUP-TFII repression provides a mechanism for increasing fetal LC steroidogenesis independent of LH/CG-stimulation to ensure masculinization, and is susceptible to disruption by environmental chemicals, stress and pregnancy hormones (in the rat). It may be that in humans, the importance of this mechanism has been over-ridden by the stimulatory effects of hCG that occur at around the time of the presumptive MPW.

The Speaker: Sander van den Driesche studied Biology at the University of Utrecht before finishing his PhD degree in molecular developmental Biology at the Hubrecht Institute in Utrecht under the supervision of Professor Christine Mummery. His PhD research was focused on the role of Endoglin in vascular remodelling in HHT (Hereditary Hemorrhagic Telangiectasia) patients. After finishing his PhD he moved to Edinburgh where he worked briefly in the lab of Dr. Colin Duncan at the Centre for Reproductive Biology (University of Edinburgh) on the hormonal regulation of the human corpus luteum, before moving to the research group of Professor Richard Sharpe in the MRC Centre for Reproductive Health at the University of Edinburgh. He is now a senior postdoctoral researcher in this group. His main interests are male reproductive health, in particular the regulation of fetal Leydig cell function and studying the underlying molecular mechanisms of Testicular Dysgenesis Syndrome disorders.