title: Folic acid uptake by the human syncytiotrophoblast is affected by gestational diabetes, hyperleptinemia, and TNF-α.
abstract: BACKGROUND
  The mechanisms whereby gestational diabetes mellitus (GDM) increases the risk of fetal overgrowth and development of metabolic diseases later in life are likely to involve changes in nutrient supply to the fetus. Hence, in this work, we hypothesize that GDM may affect folic acid (FA) supply to the placenta and fetus.
  
  
  METHODS
  We compared (3)H-FA uptake by human cytotrophoblasts isolated from normal pregnancies (normal trophoblasts; NTB cells) and GDM pregnancies (diabetic trophoblasts; DTB cells) and investigated the effect of GDM hallmarks on (3)H-FA uptake by BeWo cells.
  
  
  RESULTS
  (3)H-FA uptake by NTB and DTB cells was time dependent and acidic pH stimulated. When compared with NTB, (3)H-FA uptake by DTB cells was more sensitive to acidic pH changes and to 5-methyltetrahydrofolate and pemetrexed (PTX) inhibition, indicating a proportionally greater involvement of the proton-coupled folate transporter (PCFT). A 4-h exposure of BeWo cells to lipopolysaccharide (LPS, 1-10 μg/ml) or to high levels of tumor necrosis factor-α (TNF-α, 300 ng/l) significantly reduced (3)H-FA uptake. Moreover, hyperleptinemic conditions (100 ng/ml leptin) decreased (3)H-FA uptake by BeWo cells in a time-dependent manner when compared with normoleptinemic conditions (1 ng/ml leptin).
  
  
  CONCLUSIONS
  GDM modulates (3)H-FA uptake by the syncytiotrophoblast, and leptin as well as TNF-α downregulate it.
authors: Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
authors: João R
authors: JR
authors: Araújo
authors: Ana
authors: A
authors: Correia-Branco
authors: Liliana
authors: L
authors: Moreira
authors: Carla
authors: C
authors: Ramalho
authors: Fátima
authors: F
authors: Martel
authors: Elisa
authors: E
authors: Keating
mesh_terms: D000328:Adult; D001692:Biological Transport; D016022:Case-Control Studies; D002478:Cells, Cultured; D016640:Diabetes, Gestational / Q000097:blood / Q000378:metabolism*; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018836:Inflammation Mediators / Q000378:metabolism*; D007700:Kinetics; D020738:Leptin / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D000068437:Pemetrexed; D011247:Pregnancy; D058979:Proton-Coupled Folate Transporter / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013763:Tetrahydrofolates / Q000494:pharmacology; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D005971:Glutamates; D018836:Inflammation Mediators; D020738:Leptin; D008070:Lipopolysaccharides; D058979:Proton-Coupled Folate Transporter; D011994:Recombinant Proteins; C505058:SLC46A1 protein, human; D013763:Tetrahydrofolates; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D000068437:Pemetrexed; D006147:Guanine; D005492:Folic Acid; C005984:5-methyltetrahydrofolate