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dc.contributor.authorTarry-Adkins, Jane L
dc.contributor.authorRobinson, India G
dc.contributor.authorReynolds, Rebecca M
dc.contributor.authorAye, Irving
dc.contributor.authorCharnock-Jones, D Stephen
dc.contributor.authorJenkins, Benjamin
dc.contributor.authorKoulmann, Albert
dc.contributor.authorOzanne, Susan E
dc.contributor.authorAiken, Catherine
dc.date.accessioned2022-05-26T23:30:40Z
dc.date.available2022-05-26T23:30:40Z
dc.date.issued2022-06-17
dc.identifier.issn2296-634X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337524
dc.description.abstract<jats:p>Metformin is increasingly prescribed in pregnancy, with beneficial maternal effects. However, it is not known how metformin-treatment impacts metabolism and energy production in the developing feto-placental unit. We assessed the human placental response to metformin using both <jats:italic>in vivo</jats:italic> and <jats:italic>in vitro</jats:italic> treated samples. trophoblasts were derived from placentas collected from non-laboured Caesarean deliveries at term, then treated <jats:italic>in vitro</jats:italic> with metformin (0.01 mM, 0.1 mM or vehicle). Metformin-concentrations were measured using liquid-chromatography mass-spectrometry. Oxygen consumption in cultured-trophoblasts was measured using a Seahorse-XF Mito Stress Test. Markers of oxidative-stress were assayed using qRT-PCR. Metformin-transporter mRNA and protein-levels were determined by quantitative RT-PCR and Western-blotting respectively. Metformin concentrations were also measured in sample trios (maternal plasma/fetal plasma/placental tissue) from pregnancies exposed to metformin on clinical-grounds. Maternal and fetal metformin concentrations <jats:italic>in vivo</jats:italic> were highly correlated over a range of concentrations (R<jats:sup>2</jats:sup> = 0.76, <jats:italic>p</jats:italic> &amp;lt; 0.001; average fetal:maternal ratio 1.5; range 0.8–2.1). Basal respiration in trophoblasts was reduced by metformin treatment (0.01 mM metformin; <jats:italic>p</jats:italic> &amp;lt; 0.05, 0.1 mM metformin; <jats:italic>p</jats:italic> &amp;lt; 0.001). Mitochondrial-dependent ATP production and proton leak were reduced after treatment with metformin (<jats:italic>p</jats:italic> &amp;lt; 0.001). Oxidative stress markers were significantly reduced in primary-trophoblast-cultures following treatment with metformin. There is a close linear relationship between placental, fetal, and maternal metformin concentrations. Primary-trophoblast cultures exposed to clinically-relevant metformin concentrations have reduced mitochondrial-respiration, mitochondrial-dependent ATP-production, and reduced markers of oxidative-stress. Given the crucial role of placental energy-production in supporting fetal growth and well-being during pregnancy, the implications of these findings are concerning for intrauterine fetal growth and longer-term metabolic programming in metformin-exposed pregnancies.</jats:p>
dc.description.sponsorshipMedical Research Council New Investigator Grant (MR/T016701/1) NIHR Cambridge Biomedical Research Centre (146281) Medical Research Council (MC_UU_00014/4) (MR/R014167/1) British Heart Foundation (RG/17/12/33167) (PG/20/11/34957) (RE/18/5/34216) Next Generation Fellowship from the Centre for Trophoblast Research
dc.publisherFrontiers Media SA
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectPlacenta
dc.subjectmetformin
dc.subjecttrophoblast
dc.subjectoxidative stress
dc.subjectmitochondria, respiration
dc.subjectATP production
dc.subjectproton leak
dc.titleImpact of Metformin Treatment on Human Placental Energy Production and Oxidative Stress
dc.typeArticle
dc.date.updated2022-05-26T12:07:59Z
prism.publicationNameFrontiers in Cell and Developmental Biology
dc.identifier.doi10.17863/CAM.84939
dcterms.dateAccepted2022-05-20
rioxxterms.versionofrecord10.3389/fcell.2022.935403
rioxxterms.versionAM
dc.contributor.orcidAye, Irving [0000-0003-3400-5005]
dc.contributor.orcidAiken, Catherine [0000-0002-6510-5626]
dc.identifier.eissn2296-634X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (MR/T016701/1)
pubs.funder-project-idMRC (MC_UU_00014/4)
pubs.funder-project-idBritish Heart Foundation (RG/17/12/33167)
pubs.funder-project-idBritish Heart Foundation (PG/20/11/34957)
cam.issuedOnline2022-06-17
cam.orpheus.successMon Jun 27 07:19:02 BST 2022 - Embargo updated*
cam.orpheus.counter3
cam.depositDate2022-05-26
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2022-06-17


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International