Background
Androgen concentrations rise throughout gestation in the maternal and fetal circulations and may drive sex-specific differences in fetal growth. These sex-steroids function through the androgen receptor (AR) to transcriptionally regulate genes primarily involved in growth pathways. Indeed, current epidemiological data shows male fetuses have greater birthweight outcomes but are at a greater risk of being born small for gestational age (SGA), when compared to female fetuses, especially in the presence of pregnancy complications such as maternal asthma. The mechanisms contributing to these male-specific outcomes remain unclear; however, recent findings from our group identified sex-specific expression of a novel placental AR variant, AR-45, that may ensure appropriate male growth in uncomplicated asthmatic pregnancies (i.e. the absence of an exacerbation throughout gestation). The current study therefore focuses on characterising the function of AR-45 in the human placenta and defining its role in regulating growth in vitro.
Methodology
AR-45 cellular localisation was measured in response to 0.1nM dihydrotestosterone (DHT), as was the expression of androgen-mediated downstream targets. AR-45-overexpressing trophoblast cell proliferation was also measured in response to DHT.
Results
In vitro DHT stimulation increased total AR-45 protein and IGF-1R and IGFBP-5 mRNA. In AR-45-overexpressing cells, AR-45 was observed to localise to the nucleus upon 0.1nM DHT stimulation, and this was associated with a two-fold increase in the expression of VEGF mRNA. In contrast to endogenous protein studies, AR-45-overexpressing cells stimulated with 0.1nM DHT had reduced IGF-1R mRNA expression. Furthermore, proliferation rates of AR-45-overexpressing cells was reduced upon 0.1nM DHT stimulation, when compared to controls.
Conclusion
Our data shows AR-45 inhibits growth signalling but enhances the expression of angiogenic factors in an in vitro trophoblast model. This pathway specific function requires more investigation but may be a compensatory mechanism instituted by the placenta to ensure vasculogenesis and angiogenesis is appropriately regulated.