Research Research awards BTF Research Award 2009 The role of MCT8 in transplacental thyroid hormone transport and placental development using the knock-out mice model Dr Shiao Chan, University of Birmingham Final report Abnormalities in thyroid function are present in two and a half to five percent of pregnant women in the UK, and significantly more pregnancies are affected worldwide, especially in markedly iodine deficient areas. Thyroid disorders in women are associated with an increased risk of miscarriage, preterm labour, poor growth of the baby and stillbirth as well as poor mental development and low IQs in surviving offspring. These pregnancy complications are believed to be due to abnormal thyroid hormone activity within the placenta and the baby. However, how these complications arise is not known. We know that the mother’s thyroid hormones reach the baby by crossing the placenta, and that both the placenta and the baby require thyroid hormones for normal development. Thyroid hormones are transported in to and out of cells by transporter proteins, such as MCT8. We have recently reported that the levels of thyroid hormone transporters, such as MCT8 and MCT10, are altered in placentas obtained from human pregnancies where there is poor growth of the baby. Also, placental cells from such pregnancies show an altered response to thyroid hormone treatment. Thus, we set out in this project to perform experiments in mice that lack the thyroid hormone transporter MCT8 (MCT8 knockout mice) in order to better understand the role of MCT8 in the growth and development of the placenta and the foetus. We have found that MCT8 is widely detectable in different types of cells within the mouse placenta just as in humans. We have examined the placentas of normal mouse foetuses and compared them with those of MCT8 knockout foetuses. We found that knockout foetuses were supported by relatively larger placentas, which suggests that knockout placentas function less efficiently. Furthermore, the portion of the placenta that facilitates the transfer of oxygen and nutrients from the mother to the baby is relatively smaller in size in knockout mice. Overall, these results indicate that MCT8 plays an important role in placental and foetal growth and development. We plan to expand this work further in the immediate future to examine in more detail both the changes within the placenta and any effects on transport of thyroid hormones across the placenta in MCT8 knockout mice. This study has extended our understanding of how abnormalities in thyroid action within the placenta could lead to pregnancy complications such as poor growth of the baby. In the long term we would be able to use such research findings to refine the treatment of pregnant women with thyroid function abnormalities. There is also the possibility that we could develop new treatments for poor growth of babies through the manipulation of thyroid hormone action with the placenta. Receiving BTF funding has brought great benefit to our research group. The results of this project have complemented findings from other related studies performed by our group on MCT8 and MCT10 in the placenta, which were funded by other grant-giving bodies. This will enable us to publish our data in eminent and widely-read scientific journals to have maximum impact. It has also allowed us to strengthen our collaboration with Dr Heike Heuer (Jena, Germany) who generated the MCT8 knockout mouse model. Our continued collaboration will no doubt be fruitful in understanding the impact of MCT8 upon the placenta and reproductive outcomes. References Chan SY, Franklyn JA, Pemberton HN, Bulmer JN, Visser TJ, McCabe CJ et al. Monocarboxylate transporter 8 expression in the human placenta: the effects of severe intrauterine growth restriction. Journal of Endocrinology 2006; 189(3):465-471. Loubiere LS, Vasilopoulou E, Bulmer JN, Taylor PM, Stieger B, Verrey F et al. Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta 2010; 31(4):295-304 Vasilopoulou E, Loubiere LS, Martin-Santos A, McCabe CJ, Franklyn JA, Kilby MD et al. Differential Triiodothyronine Responsiveness and Transport by Human Cytotrophoblasts from Normal and Growth-Restricted Pregnancies. Journal of Clinical Endocrinology and Metabolism 2010; 95 (10): 4762-4770 Chan SY, Franklyn JA, Pemberton HN, Bulmer JN, Visser TJ, McCabe CJ et al. Monocarboxylate transporter 8 expression in the human placenta: the effects of severe intrauterine growth restriction. Journal of Endocrinology 2006; 189(3):465-471. A knockout mouse is a specially bred mouse in which one or more genes have been ‘turned off’ through a targeted mutation. Researchers can understand how a specific gene works by turning it off and observing the differences. Knockout mice are widely used in medical studies. The first knockout mouse was created by Mario Capecchi, Martin Evans and Oliver Smithies in 1989. They were awarded the Nobel Prize for Medicine in 2007. This study was performed on mice that lack monocarboxylate transporter 8 (MCT8). This is a thyroid hormone protein that transports T3 and T4.