ETA2022 Oral Presentations Oral Session 8: Basic 2 (5 abstracts)
Disrupted trans-placental thyroid hormone transport in a human model for MCT8 deficiency
Zhongli Chen 1 , Selmar Leeuwenburgh 2 , Wouter Zijderveld 2 , M. Broekhuizen Broekhuizen 3 , Lunbo Tan 4 , R.I. Neuman Neuman 5 , Rutchanna Jongejan 6 , Yolanda de Rijke 7 , Irwin K. Reiss 8 , A. H. J. Danser Danser 5 , Robin Peeters 9 , Marcel Meima 10 & W. Edward Visser 11
1Erasmus MC, Dept Internal Medicine,, Rotterdam, Netherlands; 2Erasmus MC, Internal Medicine, Rotterdam, Netherlands; 3Department of Pediatrics; Division of Neonatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, Division of Experimental Cardiology, Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.; 4Erasmus MC, Ointernal Medicine, Division of Pharmacology and Vascular Medicine, Rotterdam, Netherlands; 5Dept of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; 6Erasmus MC, University Medical Center, Rotterdam, The Netherlands, Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands, Rotterdam, Netherlands; 7Erasmus Medical Center, Department of Clinical Chemistry, Dept. Clinical Chemistry, Erasmus MC, University Center Rotterdam, the Netherlands, Department of Clinical Chemistry and Academic Centre for Thyroid Diseases, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands, Rotterdam, Netherlands; 8Erasmus MC University Medical Center, Divison of Neonatology, Erasmus MC-Sophia, Rotterdam, Pediatrics, Division of Neonatology, Rotterdam, Netherlands; 9Academic Center for Thyroid Diseases, Department of Endocrinology, Erasmus, Department of Internal Medicine,, Rotterdam, Netherlands; 10Dept of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, Rotterdam, Netherlands; 11Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Academic Center for Thyroid Diseases, Rotterdam, Netherlands
Objectives: During prenatal neurodevelopment, maternal-to-fetal thyroxine (T4) transfer is critical, particularly during the first half of pregnancy when the fetal thyroid gland is immature. Transcellular transport of thyroid hormones (TH) is facilitated by TH transporters. Monocarboxylate transporter 8 (MCT8) is a specific TH transporter that is crucial for transport of TH with a prominent expression at the blood-brain barrier. MCT8 deficiency is a rare disorder consisting of severe intellectual and motor disability and abnormal thyroid function tests. The transporter facilitating trans-placental TH transport is unknown. With the blood-brain barrier maturing around 18 weeks, the placental barrier may be as relevant as the blood-brain barrier for regulation of TH bioavailability for the fetal brain. We hypothesized that, should MCT8 be relevant in the placenta (a fetal-derived barrier), defective trans-placental transport of TH in MCT8 deficiency could be another additive mechanism of the disease, which might be overcome by the 3,3’,5-triiodothyronine (T3) analogue 3,3’,5-triiodothyroactic acid (TRIAC).
Methods: We tested T4 transport in human term placentas using an ex vivo placental perfusion model. We added 10 µM silychristin (a MCT8-specific inhibitor) to mimic MCT8 deficiency or vehicle as control, together with 100 nM T4 in the maternal circulation of the perfusion system. Samples were taken from both maternal and fetal circulations at different time points during a 3-hour perfusion. Next, we tested whether 100 nM TRIAC was able to cross silychristin-treated (‘’MCT8-deficient’’) placentas. T4 and reverse T3 (rT3) concentrations in perfusates were measured by radioimmunoassays. TRIAC concentrations were measured by liquid chromatography-mass spectrometry (LC-MS)/MS.
Results: Maternal-to-fetal T4 transfer was substantially reduced in the presence of silychristin (with 4.2±1.2 nM vs 10.6±0.6 nM (control) (P<0.01) fetal T4 after 3h-perfusion). TRIAC maternal-to-fetal transfer was achieved with TRIAC appearing in the fetal circulation (0 nM to 17.1±2.5 nM after 3h-perfusion).
Conclusions: MCT8 has a major role in maternal-to-fetal T4 transport. Possibly, impaired transport of T4 across the placenta in MCT8 deficiency is a key element in disturbing early fetal brain development. TRIAC is efficiently transported across the placenta and may provide preclinical support for future clinical studies of TRIAC treatment in mothers carrying fetuses with MCT8 deficiency.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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