Impact of Metformin Treatment on Human Placental Energy Production and Oxidative Stress

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Tarry-Adkins, Jane L 
Robinson, India G 
Reynolds, Rebecca M 
Charnock-Jones, D Stephen 

jats:pMetformin 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:italicin vivo</jats:italic> and jats:italicin vitro</jats:italic> treated samples. trophoblasts were derived from placentas collected from non-laboured Caesarean deliveries at term, then treated jats:italicin 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:italicin vivo</jats:italic> were highly correlated over a range of concentrations (Rjats:sup2</jats:sup> = 0.76, jats:italicp</jats:italic> &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:italicp</jats:italic> &lt; 0.05, 0.1 mM metformin; jats:italicp</jats:italic> &lt; 0.001). Mitochondrial-dependent ATP production and proton leak were reduced after treatment with metformin (jats:italicp</jats:italic> &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>

Placenta, metformin, trophoblast, oxidative stress, mitochondria, respiration, ATP production, proton leak
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Frontiers in Cell and Developmental Biology
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Frontiers Media SA
MRC (MR/T016701/1)
MRC (MC_UU_00014/4)
British Heart Foundation (RG/17/12/33167)
British Heart Foundation (PG/20/11/34957)
Medical 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