Disorders of human male reproductive health are common and growing in prevalence. These include conditions that present at birth, such as cryptorchidism (undescended testes) and hypospadias (malformed penis), as well as problems that arise in young adulthood, such as infertility/subfertility, testicular germ cell cancer (TGCC) and primary hypogonadism. The ‘testis dysgenesis syndrome’ (TDS) hypothesis proposes that these problems have a shared origin during fetal life: if the testis does not develop appropriately during a critical window of time, whilst in the womb, then both somatic and germ cell function can be affected with ramifications into adult life. Abnormalities of human sexual development (‘disorders of sex development’ or DSD), including gonadal and genital, are noted in about 1 in 200 to 1 in 300 newborns. In XY individuals, these range from mild hypospadias to complete male-to-female sex reversal.
Working in the mouse model, we have found a novel mechanism that is active during fetal life and is essential for correct development of all three major cell types present in the fetal testis. In brief, we find that a P450 enzyme, CYP26B1, must be induced at the onset of testis determination and that, in its absence, endogenous retinoic acid (RA) is not degraded leading to abnormal function of Sertoli cells (which orchestrate testis development), fetal Leydig cells (which produce steroid and peptide hormones) and germ cells (sperm precursors). Hence, we have now revealed a simple yet critical mechanism that impacts on fetal testis development as a whole. We hypothesise that this mechanism may be vulnerable to the effects of environmental chemicals.