Maternal obesity impacts fetal liver androgen signalling in a sex-specific manner

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dc.contributor.authorMeakin, A.S.
dc.contributor.authorNathanielsz, P.W.
dc.contributor.authorLi, C.
dc.contributor.authorClifton, V.L.
dc.contributor.authorWiese, M.D.
dc.contributor.authorMorrison, J.L.
dc.date.issued2024
dc.descriptionAvailable online 10 December 2023
dc.description.abstractBackground: Maternal obesity (MO) increases fetal androgen concentrations, the prevalence of macrosomia, and predisposes offspring to metabolic dysfunction in later life, especially males. These risks may be, in part, the result of increased liver-specific androgen signalling pathway activity in utero. Androgen signalling activity can be suppressed by androgen metabolism via cytochrome P450 (CYP) isoenzymes (CYP2B6, CYP3A) or through inhibition of the full-length androgen receptor (AR-FL) via the antagonistic isoform, AR-45. We hypothesised MO impairs CYP enzyme activity and AR-45 expression in male fetal livers, thereby enhancing activity of androgen signalling pathways. Methods: Nine months prior to pregnancy, nulliparous female baboons were assigned to either ad libitum control or high fat diet. At 165 day (d) gestation (term, 180 d) fetal liver was collected (n = 6/sex/group). CYP activity was quantified using functional assays; subcellular AR expression was measured using Western blot. Results: CYP2B6 and CYP3A activity, and nuclear expression of AR-45, was reduced in MO males only. Nuclear AR-45 expression was inversely related with fetal body weight of MO males only. Conclusions: Reduced CYP2B6 and CYP3A activity in conjunction with decreased nuclear AR-45 expression may enhance liver androgen signalling in males from MO pregnancies, thereby increasing the risk of macrosomia, as well as metabolic dysfunction in later life.
dc.description.statementofresponsibilityAshley S. Meakin, Peter W. Nathanielsz, Cun Li, Vicki L. Clifton, Michael D. Wiese, Janna L. Morrison
dc.identifier.citationLife Sciences, 2024; 337:122344-1-122344-9
dc.identifier.doi10.1016/j.lfs.2023.122344
dc.identifier.issn0024-3205
dc.identifier.issn1879-0631
dc.identifier.orcidClifton, V.L. [0000-0002-4892-6748]
dc.identifier.urihttps://hdl.handle.net/2440/142031
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/arc/FT170100431
dc.rights© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.source.urihttp://dx.doi.org/10.1016/j.lfs.2023.122344
dc.subjectAndrogens
dc.subjectCytochrome P450
dc.subjectFetal liver
dc.subjectMaternal obesity
dc.subject.meshLiver
dc.subject.meshHumans
dc.subject.meshFetal Macrosomia
dc.subject.meshIsoenzymes
dc.subject.meshReceptors, Androgen
dc.subject.meshAndrogens
dc.subject.meshPregnancy
dc.subject.meshFemale
dc.subject.meshMale
dc.subject.meshCytochrome P-450 CYP3A
dc.subject.meshCytochrome P-450 CYP2B6
dc.subject.meshObesity, Maternal
dc.titleMaternal obesity impacts fetal liver androgen signalling in a sex-specific manner
dc.typeJournal article
pubs.publication-statusPublished

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