From human epidemiological and related studies, there is strong (indirect) evidence that common male reproductive disorders that manifest at birth (cryptorchidism, hypospadias) or in adulthood (low sperm count, low testosterone, primary hypogonadism) may have a common origin in foetal life due to impaired androgen (testosterone) production or action; the so-called testicular dysgenesis syndrome (TDS) hypothesis. Whilst the foetal origin of cryptorchidism and hypospadias is self-evident, it is not an obvious explanation for adult onset disorders, other than for testicular germ cell cancer (TGCC). Consequently, the TDS hypothesis remains largely untested and unproven. If the TDS hypothesis was proved correct, it would refocus research effort towards identifying causal factors acting via the pregnant mother that might be preventable.
We have developed an animal model of TDS based on foetal exposure to the environmental chemical dibutyl phthalate (DBP), which causes impairment of foetal testosterone production in males. Here we use a refined version of the DBP rat model that included different time-windows of foetal exposure, such as only during the masculinisation programming window (MPW), in order to rigorously test the TDS hypothesis and to establish whether or not TDS disorders originated only within the MPW. Our results provide robust validation of the TDS hypothesis. They show that, irrespective of the endpoint evaluated (four TDS disorders, dysgenesis, anogenital distance), or the age when assessed (end of foetal life, adulthood), only disruption of testosterone production during the MPW results in TDS disorders, with all endpoints being intrinsically inter-related. In contrast, equal/greater DBP-induced suppression of testosterone production immediately after the MPW (late gestation) has no discernible effect on TDS disorders and associated endpoints. These findings have considerable human health and research implications.