Background: The mechanisms that contribute to continued male intrauterine growth in response to an adverse maternal environment, such as those brought on by maternal asthma, remain largely undefined but may, in part, be mediated by androgen-mediated signalling. We previously reported the expression of multiple AR protein isoforms in the human placenta vary in response to maternal asthma and proposed the novel AR-45 isoform to be integral in mediating male-specific androgen-dependent placental signalling. This was recently supported by work in a sheep model of maternal allergic asthma that identified AR-45 activity to be increased; however, we were unable to examine the effect of sex. Thus, in the current study we have utilised an ex vivo approach to understand sex-specific differences in placental androgen signalling in the presence and absence of inflammation using human term villous placental explants.
Methods: Explants (2mm sections; approx. 100mg wet weight) were cultured in the presence and absence of 0.1nM dihydrotestosterone (DHT), 1μg/ml lipopolysaccharide (LPS), or DHT+LPS for 24hr. Tissue was used for gene expression and subcellular AR protein isoform expression.
Results: Cytoplasmic and nuclear AR protein isoforms expression did not vary between culture conditions in either sex. AR-45 fold-change expression (normalised to untreated samples) was significantly increased in male placentae in the presence of DHT when compared with females. The activity of AR-45 was upregulated in male placentae cultured in DHT, LPS and DHT+LPS, but this was not observed in females. There were no changes in the expression of androgen-mediated downstream targets in males in response to culture conditions, but females had significantly reduced IGF1R expression in response to LPS.
Conclusion: Increased AR-45 activity in the presence of inflammation with or without androgens may drive continued male feto-placental growth in an adverse maternal environment via maintained expression of downstream growth targets.