Sexually dimorphic responses in androgen metabolism and signalling in the non-human primate placenta to moderate maternal undernutrition
Date
2025
Authors
Meakin, A.S.
Nathanielsz, P.W.
Li, C.
Clifton, V.L.
Huber, H.F.
Wiese, M.D.
Morrison, J.L.
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Biology of Sex Differences, 2025; 16(1, article no. 93):1-14
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Background Maternal nutrient restriction (MNR) can increase maternal androgen concentrations during pregnancy and cause placental dysfunction leading to reduced fetal growth, especially in males. Placental androgen metabolism, as well as differential expression and subcellular localisation of androgen receptor (AR) variants, modulates androgen signalling, which may benefit placental function; however, the impact of MNR on these adaptations remains undefined. We characterised the impact of MNR and fetal sex on placental androgen signalling in a non-human primate model of pregnancy. Methods Pregnant baboons (Papio spp.) were randomly assigned to control diet (Ctrl; offspring female n = 5, male n = 6) or MNR diet (70% of global Ctrl; offspring female n = 5, male n = 5) at 0.16 gestation (term = similar to 180 days). Fetuses were delivered by Caesarean section at 0.9 gestation and placenta collected. Molecular measures of sex steroid signalling and placental function were quantified using established LC-MS/MS assays, Western blot, and qRT-PCR. Data were analysed using two-way ANOVA (factors: diet, sex) with Tukey's multiple comparison test. Results CYP17A1, SRD5A1, and PGF expression was higher, whereas HSD3B1, CYP19A1, and ANGPT2 was lower in male compared to female placentae, independent of diet. KDR expression and CYP19A1 activity increased in MNR versus Ctrl in females only. Cytoplasmic expression of the antagonistic AR variant, AR-45, was higher in males, whereas MNR increased cytoplasmic and nuclear AR-45 expression independent of sex. Conclusions Differences in placental steroidogenic and angiogenic genes, as well as androgen metabolism and signalling, may explain sex-specific placental responses to MNR. Better understanding of molecular regulators of androgen signalling may lead to novel, targetable therapeutics that improve placental function in complicated pregnancies associated with increased androgen concentrations.
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Copyright 2025 The Author(s)