Environmental chemicals and reproductive disorders in the human male
Richard M Sharpe, Chris McKinnell, Nina Hallmark, Ana Rivas, & Jane S Fisher
MRC Human Reproductive Sciences Unit,
Although testicular differentiation is a hormonally independent process, subsequent sexual differentiation/masculinization is a totally hormone-dependent process. As a result, this process is inherently susceptible to 'endocrine disruption' (in contrast to the female fetus). Androgens play the key role in masculinization, and impairment of androgen production or action can consequently impair this process. Oestrogens may also play a role as oestrogen receptors (ER) are as widely distributed in the developing reproductive system as are androgen receptors. Based on animal and human studies, over-exposure to potent oestrogens during early pregnancy can impair reproductive development, raising the possibility that environmental oestrogens could interfere with male sexual differentiation. However, our recent evidence suggests that oestrogen impairment of male reproductive development requires parallel suppression of androgen production and action, and this is only caused by exposure to very high levels of potent (not environmental) oestrogens.
It has been proposed that, in the human, cryptorchidism, hypospadias, testicular cancer and some cases of low sperm counts may form a 'testicular dysgenesis syndrome' (TDS) with a common origin in fetal life. Abnormal function of Sertoli and Leydig cells and altered androgen (and possibly oestrogen) action are thought to underlie TDS. Exactly how this occurs is unclear, as androgens probably play only minor roles in fetal testis development. However, following on from earlier studies by others, we have shown that treatment of pregnant rats with 500mg/kg dibutyl phthalate (DBP) can result in a TDS phenotype with a >60% incidence of (mainly unilateral) cryptorchidism, hypospadias, infertility and abnormal fetal germ cell development; fetal testicular testosterone levels were reduced by ~90%. Using cell-specific markers and confocal microscopy we have charted development of the different testicular cell types following DBP exposure. These studies have revealed focal testicular dysgenesis in which Sertoli, peritubular and Leydig cells are intermixed with gonocytes in areas in which incomplete seminiferous cord formation has occurred. Sertoli cell-only (SCO) tubules were found focally (scrotal testes) or were widespread (cryptorchid testes) in association with persistence of immature Sertoli cells. Intratubular Leydig cells and Leydig cell hyperplasia were also found, most commonly in association with dysgenetic areas. All of these changes were evident from fetal life through to adulthood. Numerous multinucleated gonocytes were observed in perinatal life but disappeared by postnatal day 10.
Exposure of rats to a lower dose of DBP (100mg/kg), which did not cause cryptorchidism or hypospadias, still resulted in detectable testicular changes perinatally, including induction of widespread multinucleated gonocytes, abnormal aggregation of Leydig cells and mis-segregation of Sertoli cells. In adulthood, ~30% of such animals exhibited variable numbers of SCO tubules and subfertility, though testis weight was normal. The changes observed after DBP treatment of rats are remarkably similar to those reported in human TDS, including the observation that changes to spermatogenesis/fertility may be the most sensitive endpoint affected by treatment. Identification of the mechanisms involved in DBP induction of the above changes should therefore provide valuable insights into human TDS and may enable identification of potential causal factors. Whether or not phthalates might play a role in human TDS is also being addressed by comparative fetal testis studies in vitro.