The regulation and dysregulation of fetal gonad development
Links between declining human male fertility (decreased sperm counts, increased incidence of both testicular cancer and genital abnormalities) and the increasing prevalence of endocrine disrupting chemicals (EDCs) in the environment have been reported. We aim to characterise the key developmental processes occurring during human fetal gonad development. Human fetal testis development was characterised by a transient increase in interstitial area proliferation between 13-19 weeks which was accompanied by an increase in steroidogenic acute regulatory protein (StAR) and steroidogenic enzymes. Androgen receptor was expressed by the peritubular myoid cells which had a high bcl-2:bax ratio, indicative of cell survival. Estrogen receptors ( and ) were localised to distinct cell populations. In the ovine gonad similar developmental processes occurred, and comparison with human ovarian development demonstrated interesting parallels. After optimisation, the explant culture system revealed that exposure to the insecticidal EDC dieldrin, at low (<1 ppb) doses reduced LH-stimulated testosterone output in the human fetal testis. This was accompanied by dose-specific changes to the testis proteome, alterations in bcl-2:bax ratios in favour of apoptosis and a down-regulation in StAR expression relative to the LH-treated controls. In conclusion, the processes of proliferation apoptosis, steroidogenesis and steroid action are crucial during fetal gonad development. We demonstrated that in utero exposure to dieldrin may cause reproductive dysfunction in adult life due to reduced steroidogenesis in the fetal gonad; mediated through a down-regulation in StAR expression and alterations in the regulation of gonadal apoptosis.