Speaker abstracts: S01: New insights into fetal masculinisation disorders and the implications for endocrine disruptor effects

Abstract

Becoming a male is ultimately determined by androgen-induced masculinisation. Disorders of this, resulting in hypospadias (abnormal penis development) or cryptorchidism (undescended testes), are common disorders in humans. Together with adult onset disorders (low sperm counts, testis germ cell cancer) hypospadias and cryptorchidism may constitute a testicular dysgenesis syndrome (TDS) in humans, with a proposed common fetal origin that may involve deficiencies in androgen production or action. As animal evidence has shown that anti-androgenic endocrine disruptors (EDs) can induce TDS-like effects, concern has grown regarding their potential involvement in human TDS disorders. We have developed a rat model of TDS, in which we have begun to dissect the fetal mechanisms that underlie TDS disorders. Using another rat model in which androgen action is blocked by the anti-androgen flutamide, we have recently identified a ‘male programming window’, which available evidence suggests occurs also in the human fetus (between ∼8 and 12 week's gestation). Androgens must act within this programming window to set up later correct development of the reproductive tract and genitalia. Surprisingly, androgen-driven (abnormal) masculinisation of females is confined to the same programming window as for normal males. Blocking androgen action only within the programming window induces hypospadias and cryptorchidism and alters penile length in males; these all correlate with reduction in anogenital distance (AGD), which provides a non-invasive, lifelong read-out of androgen exposure in the programming window (but not later in gestation). As AGD is measurable in human newborns/neonates, it may predict adult onset TDS disorders and provide clinically important insights into reproductive tract masculinisation and its disorders. With this new understanding we have also begun to explore the role and timescale of effects of androgens in regulation of penile development and size. We show in the rat, that AGD predicts fetal and adult testis size (and thus sperm production), but the mechanism underlying this is unknown as it is not explained by effects on Sertoli cell number, as androgen regulation of Sertoli cell proliferation extends beyond the ‘male programming window’ (when AGD is determined); this relationship is of potential importance in the context of fetal origins of low sperm counts in humans. These findings strongly support the view that deficient fetal androgen action is a key feature of TDS. We postulate that delayed onset of fetal testosterone production may also be important in TDS. These new findings have considerable implications with regard to the time-window of susceptibility of the fetal male to disruption by EDs.