The role of monocarboxylate transporter 8 during human placental development in normal and IUGR pregnancies
Lead Research Organisation:
University of Birmingham
Department Name: Reproductive and Child Health
Abstract
There is a link between mild underactive thyroid gland activity in pregnant women and delayed mental development in offspring. Further investigation suggests that
maternal thyroid hormone (TH) has a direct effect on the baby’s brain development. This would rely on a well-functioning placenta to transport TH from the mother to the baby. Placental development itself is also influenced by TH, including a critical stage when the blood vessels within the wall of the womb are invaded by placental cells in order to form an effective placenta for exchange of essential factors between the mother and baby. In abnormal pregnancies where babies are not growing well (IUGR), impaired growth often stems from disruptions in placental development. Indeed, disorders of the thyroid gland in women are associated with an increased risk of placental disorders such as IUGR as
well as miscarriages, stillbirths and placental bleeding. Currently, our understanding of how the placenta transports TH and how the development of the placenta is affected by TH is very poor. Although the level of TH in the mother’s blood is a crucial factor, there are other factors which can modulate the effects of TH. One of these factors includes a protein found on cell surfaces called MCT8, which is a potent transporter of TH into cells. We aim to clarify the role of MCT8 within the placenta by studying its presence in human placenta and investigating differences between normal and IUGR pregnancies. We also propose to assess how MCT8 affects the properties of placental cells. Worldwide, disruptions in thyroid gland activity during pregnancy and IUGR are common findings, thus this proposed research would have widespread implications.
maternal thyroid hormone (TH) has a direct effect on the baby’s brain development. This would rely on a well-functioning placenta to transport TH from the mother to the baby. Placental development itself is also influenced by TH, including a critical stage when the blood vessels within the wall of the womb are invaded by placental cells in order to form an effective placenta for exchange of essential factors between the mother and baby. In abnormal pregnancies where babies are not growing well (IUGR), impaired growth often stems from disruptions in placental development. Indeed, disorders of the thyroid gland in women are associated with an increased risk of placental disorders such as IUGR as
well as miscarriages, stillbirths and placental bleeding. Currently, our understanding of how the placenta transports TH and how the development of the placenta is affected by TH is very poor. Although the level of TH in the mother’s blood is a crucial factor, there are other factors which can modulate the effects of TH. One of these factors includes a protein found on cell surfaces called MCT8, which is a potent transporter of TH into cells. We aim to clarify the role of MCT8 within the placenta by studying its presence in human placenta and investigating differences between normal and IUGR pregnancies. We also propose to assess how MCT8 affects the properties of placental cells. Worldwide, disruptions in thyroid gland activity during pregnancy and IUGR are common findings, thus this proposed research would have widespread implications.
Technical Summary
Studies investigating the link between maternal thyroid status and neurodevelopmental delay in offspring suggest a direct effect of maternal thyroid hormone (TH) on fetal brain development, which would rely on a well-functioning placenta for transplacental supply of TH. Placental development, including the trophoblastic invasion of the uterine spiral arteries to transform them into high-flow low-resistance vessels for effective maternal-fetal exchange, is itself TH-responsive as evidenced by in-vitro trophoblast studies. However, the molecular mechanisms mediating these processes remain poorly understood. Whilst circulating maternal THs are the major determinants of transplacental fetal TH supply and placental cell supply of the active ligand, triiodothyronine (T3), other factors modulate them including the plasma membrane transport of TH, the expression of iodothyronine deiodinase enzymes and thyroid hormone receptors (TRs). Intrauterine growth restriction (IUGR) contributes significantly to perinatal and neonatal mortality and morbidity. IUGR is associated with fetal hypothyroxinaemia and is accompanied by malplacentation with at least 50% of spiral arteries remaining ?untransformed?.
Hypothesis:
1) Monocarboxylate transporter 8 (MCT8), the most powerful TH plasma membrane transporter, plays an important role in both the transplacental transport of TH and TH-dependent placental development.
2) In the pathological state of IUGR, increased MCT8 and TR expression occurs as a compensatory mechanism attempting to facilitate TH action in trophoblasts.
Key experimental aims:
1) to define the gestational ontogeny and cellular localisation of MCT8, as well as its co-localisation with deiodinases and TRs in human villous placenta and placental bed from the first, second and third trimesters of pregnancy. We will compare differences between IUGR and normal placenta in the third trimester.
2) to investigate whether MCT8 transports factors in addition to TH (as suggested by observations of MCT8 in neurodevelopment).
3) to assess the effects of the level of MCT8 expression on the proliferation, survival and uterine invasion properties of primary cytotrophoblasts and extravillous trophoblasts.
4) to compare TH transport and functional characteristics [as in (3)] of primary cytotrophoblast from IUGR placenta with those from normal placenta.
5) to use gene arrays to identify thyroid hormone responsive genes and their downstream gene transcription effects in primary cytotrophoblasts, as well as assessing the broader T3-independent response modulated by MCT8 effects.
Conclusion:
These experiments will clarify the role of MCT8 in villous and extravillous trophoblasts, and how alterations in the level of MCT expression can affect placental development.
Hypothesis:
1) Monocarboxylate transporter 8 (MCT8), the most powerful TH plasma membrane transporter, plays an important role in both the transplacental transport of TH and TH-dependent placental development.
2) In the pathological state of IUGR, increased MCT8 and TR expression occurs as a compensatory mechanism attempting to facilitate TH action in trophoblasts.
Key experimental aims:
1) to define the gestational ontogeny and cellular localisation of MCT8, as well as its co-localisation with deiodinases and TRs in human villous placenta and placental bed from the first, second and third trimesters of pregnancy. We will compare differences between IUGR and normal placenta in the third trimester.
2) to investigate whether MCT8 transports factors in addition to TH (as suggested by observations of MCT8 in neurodevelopment).
3) to assess the effects of the level of MCT8 expression on the proliferation, survival and uterine invasion properties of primary cytotrophoblasts and extravillous trophoblasts.
4) to compare TH transport and functional characteristics [as in (3)] of primary cytotrophoblast from IUGR placenta with those from normal placenta.
5) to use gene arrays to identify thyroid hormone responsive genes and their downstream gene transcription effects in primary cytotrophoblasts, as well as assessing the broader T3-independent response modulated by MCT8 effects.
Conclusion:
These experiments will clarify the role of MCT8 in villous and extravillous trophoblasts, and how alterations in the level of MCT expression can affect placental development.