Reduced thyroid hormone transport in a human placental model with inhibited MCT8

Maternal-to-fetal transfer of the thyroid hormone T4 is essential for prenatal neurodevelopment, but the transporter facilitating trans-placental T4 transport is unknown. Mutations in the thyroid hormone transporter MCT8 cause a neurodevelopmental and metabolic disorder, of which key clinical features can be ameliorated by the T3 analog TRIAC. Should placental MCT8 be physiologically relevant, defective T4 transport across the placenta, which is fetal-derived tissue, could represent a hitherto unrecognized mechanism underlying MCT8 deficiency. We investigated the importance of MCT8 and the trans-placental transport of TRIAC using an ex vivo human placental perfusion setup.

Uncomplicated term placentas were used for the ex vivo dual perfusion experiments to investigate the maternal-to-fetal transfer of T4 or TRIAC in the absence or presence of the MCT8 inhibitor silychristin. Samples were collected at various time points from both maternal and fetal circulations. T4 and rT3 concentrations in the perfused samples were measured using radioimmunoassay and TRIAC using LC-MS/MS.

In the presence of silychristin, maternal-to-fetal transfer of 100 nM T4 was reduced by ∼60% (4.2 ± 1.2 nM fetal T4 in MCT8-inhibited placentas versus 10.6 ± 0.6 nM fetal T4 in control placentas). TRIAC was efficiently transferred from the maternal to the fetal circulation.

Our study i) shows that MCT8 has a major role in maternal-to-fetal T4 transport, ii) implies that disrupted placental transport of thyroid hormones may contribute to neurodevelopmental delays in MCT8 deficiency and iii) indicates that TRIAC is efficiently transported across the placenta, independent of MCT8, holding potential in prenatal treatment in mothers carrying fetuses with MCT8 deficiency.