Fetal Leydig cell (LC) dysfunction leads to human male reproductive disorders (testicular dysgenesis syndrome; TDS) that manifest at birth (cryptorchidism, hypospadias) or in young adulthood (low sperm count, testicular germ cell cancer). The factors regulating fetal LC function in early gestation are unknown, but can be disrupted in rats by environmental chemicals (e.g. dibutyl phthalate (DBP)). We identify a novel repressor mechanism that explains this vulnerability, which may represent a mechanism underpinning TDS disorders. In rats, intratesticular testosterone (ITT) and fetal LC size increase ~3-fold between e15.5e21.5, associated with a progressive decrease in LC nuclear expression of Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII), which competes for binding sites in gene promoters with steroidogenic factor 1 (SF-1). Reductions in fetal ITT in rats induced by DBP, diethylstilbestrol or dexamethasone are all associated with maintenance/induced LC nuclear expression of COUP-TFII. Conversely, lack of effect of DBP on LC COUP-TFII expression explains absence of ITT decrease in mice. Nuclear COUP-TFII expression in fetal LC relates inversely to expression of SF-1-dependent genes (StAR, Cyp11a1, Cyp17a1) that have overlapping sites for SF-1 and COUP-TFII in their promoter regions, but does not affect a LC gene (3β-HSD) that lacks such sites, nor an SF-1 dependent gene (Amh) in Sertoli cells (that lack COUP-TFII expression). In human fetal LC, similar age-related decline in expression of COUP-TFII is evident as in the rat. We propose that relief of COUP-TFII repression provides a mechanism for increasing fetal LC steroidogenesis to ensure masculinization, but is susceptible to disruption by environmental chemicals, stress and pregnancy hormones (in the rat).
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.