Pathways of endocrine disruption during male sexual differentiation and masculinisation

After testis formation, further development of a male phenotype (masculinisation) is driven by three hormones from the foetal testis: anti-Müllerian hormone, insulin-like factor 3, and testosterone. These hormones divert the development of reproductive and other organs from female to male and also play a role in testis development. The hormone dependence of masculinisation renders this process inherently susceptible to disruption by factors that interfere with hormone production, bioavailability, metabolism, or action. This susceptibility is illustrated by the high prevalence of congenital masculinisation disorders (cryptorchidism, hypospadias) and disorders in young adult men (low sperm counts, testis cancer), which may also stem from maldevelopment (dysgenesis) of the foetal testis. Testicular dysgenesis occurring in humans, or which is induced in animal models by foetal exposure to certain phthalates, is associated with impaired hormone production by the foetal testis. There is currently no definitive evidence that exposure of humans to environmental chemicals can induce testicular dysgenesis and/or impair masculinisation, though pathways via which this could potentially occur are established.

Keywords: testis formation, testicular dysgenesis, seminiferous cord formation, Sertoli cells, Leydig cells, foetal germ cells, anti-Müllerian hormone, insulin-like factor 3, testosterone, dihydrotestosterone, oestradiol, cryptorchidism, hypospadias, low sperm counts, testis cancer, phthalates