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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.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.subjectoxidative stress
dc.subjectmitochondria, respiration
dc.subjectATP production
dc.subjectproton leak
dc.titleImpact of Metformin Treatment on Human Placental Energy Production and Oxidative Stress
prism.publicationNameFrontiers in Cell and Developmental Biology
dc.contributor.orcidAye, Irving [0000-0003-3400-5005]
dc.contributor.orcidAiken, Catherine [0000-0002-6510-5626]
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.orpheus.successMon Jun 27 07:19:02 BST 2022 - Embargo updated*
pubs.licence-display-nameApollo Repository Deposit Licence Agreement

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