Folic acid uptake by the human syncytiotrophoblast is affected by gestational diabetes, hyperleptinemia, and TNF-α

Abstract

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. 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. (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). GDM modulates (3)H-FA uptake by the syncytiotrophoblast, and leptin as well as TNF-α downregulate it.