Oral Presentation 46th Annual Meeting of the Fetal and Neonatal Physiological Society 2019

Altered placental androgen signalling contributes to growth restricted outcomes (#10)

Vicki L Clifton 1 , Ashley R Meakin 1 , Zarqa Saif 1 , Martha Lappas 2
  1. Mater Research Institute, University of Queensland, Brisbane, QLD, Australia
  2. Obstetrics, Mercy Hospital, Melbourne, VIC, Australia

Background

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. The mechanisms contributing to these male-specific outcomes remain unclear but may be mediated, in part, by altered placental androgen signalling. Our group recently identified sex-specific expression of multiple androgen receptor (AR) isoforms in the human placenta that may modulate placental androgen signalling. Specifically, expression of a 45kDa variant, AR-45, was associated with growth outcomes in males only. We have questioned whether altered AR-45 expression and localisation contributes to perturbations in growth outcomes. Therefore, this study has investigated the function of AR-45 in vitro and also characterised its expression and localisation in growth restricted placentae.

Methodology

Cellular localisation of AR-45 in response to 0.1nM DHT was analysed, as was the expression of androgen-mediated downstream targets. Cellular proliferation in AR-45-overexpressing trophoblast cells in response to increasing concentrations of dihydrotestosterone (DHT) was also analysed. Protein and mRNA of appropriate for gestational age (AGA) (n=28) and SGA (n=84) placentae were used to identify AR protein levels and androgen-mediated downstream target gene expression.

Results

AR-45-overexpressing trophoblast cells had reduced proliferation, reduced certain growth factor gene expression, but significantly increased VEGF mRNA expression. There was a significant increase in cytoplasmic AR-45 in male placentae from severe SGA neonates (<5th birthweight centile (BWC)), when compared to moderate SGA (5th – 10th BWC) and AGA (>10th BWC). Cytoplasmic-localised placental AR-45 trended towards a negative association with BWC in males (r2 = -0.294, p = 0.059) only.

Conclusion

Our data shows AR-45 suppresses growth signalling but may be involved in the transcriptional regulation of angiogenic factors. It is postulated that alterations to androgen signalling, via cytoplasmic sequestering of AR-45, may contribute to growth restricted outcomes via perturbed placental vasculature.