Background: Thyroid hormones (TH) are vital for fetal and placental development. TH transporters including monocarboxylate transporters 8 and 10 (MCT8, MCT10), organic anion transporters (OATP1A2, OATP4A1) and system-L amino acid transporters (LAT1, LAT2) are expressed in human placenta from 6 weeks of gestation. All of these TH transporters have been localized to the human syncytiotrophoblast layer of placental villi, which is in direct contact with maternal blood. Thyroxine (T4) is postulated to be the major TH transported from the maternal circulation to fetal circulation. This study aims to determine the contribution of each TH transporter to T4 uptake at the apical membrane of syncytiotrophoblasts.
Methods and results: Maternal-facing syncytiotrophoblast microvillous plasma membranes (MVM) were isolated from normal human term placentae by Mg2+ precipitation and differential centrifugation. MCT10, MCT8, OATP1A2, OATP4A1 and LAT1 protein were detected in MVM using western-blot. [125I]T4 uptake by MVM vesicles was linear over the first 2 min and reached equilibrium after 20 min. T4 uptake was Na+-independent. Excess T4 reduced [125I]T4 uptake by 22% (n=5, P<0.05). T3 did not affect [125I]T4 uptake whereas TRIAC significantly reduced [125I]T4 uptake by 19% (n=3, P<0.01). Competitive inhibitors of TH transport by MCT10, LATs and OATPs, such as tryptophan, leucine, probenecid and bromosulphtalein, alone, did not affect [125I]T4 uptake significantly. However, combinations of these inhibitors could significantly affect [125I]T4 uptake. The strongest inhibition of T4 uptake was achieved with desipramine, a non-competitive inhibitor of TH transport mediated by MCT8, MCT10 and LAT1 (31%, n=4, P<0.05).
Conclusion: In human term placenta, TH transporters are ubiquitously present in syncytiotrophoblast MVM, which can regulate placental TH entry and transplacental TH transfer from the mother to the fetus. Our data suggest that maternal T4 uptake by syncytiotrophoblasts is not mediated by a single predominant TH transporter but rather by a combination of these proteins.