Abstract
Monocarboxylate transporter 8 (MCT8) is a well-established thyroid hormone (TH) transporter. In humans, MCT8 mutations result in changes in circulating TH concentrations and X-linked severe global neurodevelopmental delay. MCT8 is expressed in the human placenta throughout gestation, with increased expression in trophoblast cells from growth-restricted pregnancies. We postulate that MCT8 plays an important role in placental development and transplacental TH transport. We investigated the effect of altering MCT8 expression in human trophoblast in vitro and in a Mct8 knockout mouse model. Silencing of endogenous MCT8 reduced T3 uptake into human extravillous trophoblast-like cells (SGHPL-4; 40%, P<0.05) and primary cytotrophoblast (15%, P<0.05). MCT8 over-expression transiently increased T3 uptake (SGHPL-4∶30%, P<0.05; cytotrophoblast: 15%, P<0.05). Silencing MCT8 did not significantly affect SGHPL-4 invasion, but with MCT8 over-expression T3 treatment promoted invasion compared with no T3 (3.3-fold; P<0.05). Furthermore, MCT8 silencing increased cytotrophoblast viability (∼20%, P<0.05) and MCT8 over-expression reduced cytotrophoblast viability independently of T3 (∼20%, P<0.05). In vivo, Mct8 knockout reduced fetal:placental weight ratios compared with wild-type controls at gestational day 18 (25%, P<0.05) but absolute fetal and placental weights were not significantly different. The volume fraction of the labyrinthine zone of the placenta, which facilitates maternal-fetal exchange, was reduced in Mct8 knockout placentae (10%, P<0.05). However, there was no effect on mouse placental cell proliferation in vivo. We conclude that MCT8 makes a significant contribution to T3 uptake into human trophoblast cells and has a role in modulating human trophoblast cell invasion and viability. In mice, Mct8 knockout has subtle effects upon fetoplacental growth and does not significantly affect placental cell viability probably due to compensatory mechanisms in vivo.
Highlights
The importance of maternal thyroid hormone (TH) availability to normal fetoplacental development is highlighted by the association of untreated maternal thyroid dysfunction with pregnancy complications, including miscarriage, pre-eclampsia, intrauterine growth restriction (IUGR) and stillbirth [1,2,3,4]
monocarboxylate transporter 8 (MCT8) silencing was associated with a significant reduction in T3 uptake by SGHPL-4 cells (Figure 1A) with a maximum effect at 10 minutes (40% reduction, P,0.05)
At 30 minutes net T3 uptake was similar in MCT8-transfected cells and in vector only (VO) controls, presumably because equilibrium was reached by that point
Summary
The importance of maternal thyroid hormone (TH) availability to normal fetoplacental development is highlighted by the association of untreated maternal thyroid dysfunction with pregnancy complications, including miscarriage, pre-eclampsia, intrauterine growth restriction (IUGR) and stillbirth [1,2,3,4]. These complications are often characterized by malplacentation or uteroplacental insufficiency. The human placenta is thought to be TH-responsive [5], as evidenced by the expression of the full complement of proteins that are required to mediate TH action from early gestation onwards. The human placenta demonstrates pre-receptor regulation by deiodinase enzymes type 2 (D2; converts thyroxine [T4] to T3) and type 3 (D3; inactivates T4 and T3) [10] with the latter playing a critical role in regulating the transplacental passage of TH [11]
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