Sex-specific effects of betamethasone on glucocorticoid and apoptotic signalling pathways in the sheep placenta

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dc.contributor.authorMeakin, A.S.
dc.contributor.authorLock, M.C.
dc.contributor.authorHolman, S.L.
dc.contributor.authorRobinson, J.L.
dc.contributor.authorClifton, V.L.
dc.contributor.authorRoberts, C.T.
dc.contributor.authorWiese, M.D.
dc.contributor.authorGatford, K.L.
dc.contributor.authorMorrison, J.L.
dc.date.issued2025
dc.description.abstractAntenatal corticosteroid therapy (ACS, e.g. betamethasone) is standard clinical care for pregnancies at risk of preterm delivery to reduce the incidence of neonatal lung disease and death. Variable and sex-specific impacts ofACS on the placenta have been reported andmay reflect differing expression profiles of glucocorticoid receptor (GR) isoforms. We therefore examined placental GR isoforms and molecular and structural responses to betamethasone in the clinically relevant sheep pregnancy. Pregnant Merino ewes at 138 days of gestation (term = 150 days) received i.m. injections of saline or 11.6 mg of betamethasone 48 and 24 h prior to Caesarean section delivery of lambs and tissue collection. Placental glucocorticoid concentrations were measured using liquid chromatography-tandem mass spectrometry. Markers of GR signalling and placental development and function were measured using histology, western blotting and quantitative real-time PCR. Betamethasone increased diffusion barrier thickness in female placentae only and reduced placental cortisol concentrations in both sexes. Betamethasone increased cytoplasmic GRαC, GR-P and GRαD isoforms in female placentae only; neither treatment nor sex impacted nuclear GR isoform expression. Expression of angiogenic genes was higher, whereas that of growth-promoting genes was lower, in betamethasone-exposed placentae, independent of sex. Similarly, expression of endoplasmic reticulum stress genes was lower in betamethasone-exposed than control placentae, whereas those involved in oxidative stress and apoptosis were higher, particularly in females. Betamethasone induced molecular changes in the placenta within 48 h of exposure. The apoptotic response was heightened in female placentae, possibly driven by higher expression of specific GR isoforms, which contributes to a greater risk of ACS-induced placental insufficiency.
dc.description.statementofresponsibilityAshley S. Meakin, Mitchell C. Lock, Stacey L. Holman, Joshua L. Robinson, Vicki L. Clifton, Claire T. Roberts, Michael D.Wiese, Kathryn L.Gatford, and Janna L. Morrison
dc.identifier.citationJournal of Physiology, 2025; 603(17):4867-4886
dc.identifier.doi10.1113/JP289044
dc.identifier.issn0022-3751
dc.identifier.issn1469-7793
dc.identifier.orcidClifton, V.L. [0000-0002-4892-6748]
dc.identifier.orcidRoberts, C.T. [0000-0002-9250-2192]
dc.identifier.orcidGatford, K.L. [0000-0002-2823-3004]
dc.identifier.urihttps://hdl.handle.net/2440/147720
dc.language.isoen
dc.publisherWiley
dc.relation.granthttp://purl.org/au-research/grants/arc/FT170100431
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1136100
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1174971
dc.rights© 2025 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.source.urihttps://doi.org/10.1113/jp289044
dc.subjectbetamethasone; fetus; glucocorticoid receptor; placenta; sex differences; sheep
dc.subject.meshPlacenta
dc.subject.meshAnimals
dc.subject.meshSheep
dc.subject.meshBetamethasone
dc.subject.meshReceptors, Glucocorticoid
dc.subject.meshGlucocorticoids
dc.subject.meshSex Factors
dc.subject.meshSignal Transduction
dc.subject.meshApoptosis
dc.subject.meshPregnancy
dc.subject.meshSex Characteristics
dc.subject.meshFemale
dc.subject.meshMale
dc.titleSex-specific effects of betamethasone on glucocorticoid and apoptotic signalling pathways in the sheep placenta
dc.typeJournal article
pubs.publication-statusPublished

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