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

Frontiers in Cell and Developmental Biology

D. Stephen Charnock-Jones¹  Irving L. M. H. Aye¹  India G. Robinson²  Jane L. Tarry-Adkins²  Rebecca M. Reynolds³  Susan E. Ozanne⁴  Albert Koulmann⁴  Benjamin Jenkins⁴  Catherine E. Aiken⁴ 

[1] Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom;Department of Obstetrics and Gynaecology, The Rosie Hospital and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom;Queen’s Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom;Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, Addenbrooke’s Hospital, University of Cambridge, Cambridge, United Kingdom;

关键词: placenta;    metformin;    trophoblast;    oxidative stress;    mitochondria;    respiration;   

DOI  :  10.3389/fcell.2022.935403

来源: DOAJ

【 摘 要 】

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 in vivo and in vitro treated samples. trophoblasts were derived from placentas collected from non-laboured Caesarean deliveries at term, then treated in vitro 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 in vivo were highly correlated over a range of concentrations (R2 = 0.76, p < 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; p < 0.05, 0.1 mM metformin; p < 0.001). Mitochondrial-dependent ATP production and proton leak were reduced after treatment with metformin (p < 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.

【 授权许可】

Unknown