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School of Medicine, Conjoint Endocrine Laboratory, Disciplines of Medicine, The University of Queensland, Herston, 4006 Brisbane, Queensland, Australia
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School of Medicine, Conjoint Endocrine Laboratory, Disciplines of Medicine, The University of Queensland, Herston, 4006 Brisbane, Queensland, Australia
School of Medicine, Conjoint Endocrine Laboratory, Disciplines of Medicine, The University of Queensland, Herston, 4006 Brisbane, Queensland, Australia
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School of Medicine, Conjoint Endocrine Laboratory, Disciplines of Medicine, The University of Queensland, Herston, 4006 Brisbane, Queensland, Australia
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The development of fetal thyroid function is dependent on the embryogenesis, differentiation, and maturation of the thyroid gland. This is coupled with evolution of the hypothalamic–pituitary–thyroid axis and thyroid hormone metabolism, resulting in the regulation of thyroid hormone action, production, and secretion. Throughout gestation there is a steady supply of maternal thyroxine (T4) which has been observed in embryonic circulation as early as 4 weeks post-implantation. This is essential for normal early fetal neurogenesis. Triiodothyronine concentrations remain very low during gestation due to metabolism via placental and fetal deiodinase type 3. T4 concentrations are highly regulated to maintain low concentrations, essential for protecting the fetus and reaching key neurological sites such as the cerebral cortex at specific developmental stages. There are many known cell membrane thyroid hormone transporters in fetal brain that play an essential role in regulating thyroid hormone concentrations in key structures. They also provide the route for intracellular thyroid hormone interaction with associated thyroid hormone receptors, which activate their action. There is a growing body of experimental evidence from rats and humans to suggest that even mild maternal hypothyroxinemia may lead to abnormalities in fetal neurological development. Our review will focus on the ontogeny of thyroid hormone in fetal development, with a focus on cell membrane transporters and TR action in the brain.
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ABSTRACT
We investigated the uptake of l-tri-iodothyronine (T3) by cultured human trophoblast cells. Uptake was time-dependent, initially linear and approaching equilibrium after 60 min with an approximate half-time of 13 ± 4·5 min (mean ± s.e.m., n = 4). It had a non-saturable component accounting for about 50% of total uptake. We demonstrated a single saturable T3 uptake mechanism with a calculated Michaelis constant (K m) of 755 ± 145 nmol/l (n = 11–13) and a corresponding maximum velocity of 28·8 ± 5·3 pmol/min per mg protein (n = 11–13). The K m value was similar to those reported in other tissues.
Journal of Endocrinology (1992) 133, 483–486
School of Medicine, Conjoint Endocrine Laboratory, Disciplines of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Herston, Brisbane, Queensland 4029, Australia
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School of Medicine, Conjoint Endocrine Laboratory, Disciplines of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Herston, Brisbane, Queensland 4029, Australia
School of Medicine, Conjoint Endocrine Laboratory, Disciplines of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Herston, Brisbane, Queensland 4029, Australia
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School of Medicine, Conjoint Endocrine Laboratory, Disciplines of Medicine, Royal Brisbane and Women's Hospital, The University of Queensland, Herston, Brisbane, Queensland 4029, Australia
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Transplacental delivery of maternal thyroid hormones to the fetus, in particular thyroxine (T4), is critical in ensuring normal fetal neurological development. The fetus relies on maternal T4 till around 16 weeks gestation, but mechanisms of placental T4 transport are not yet fully elucidated. Placenta produces, secretes and takes up the thyroid hormone-binding protein transthyretin (TTR). Many placental genes are regulated by oxygen levels, which are relatively low (1%) in the early first trimester, rising to 3% in the mid first trimester and 8% in the early second trimester and thereafter. We examined the expression and uptake of TTR in isolated primary human placental cytotrophoblast cells cultured under different oxygen concentrations (1, 3, 8, 21% O2 and 200 μM desferrioxamine (DFO)) for 24 h. We observed sevenfold higher expression of TTR mRNA and protein levels at 1% O2 than at 8 and 21% O2. Significant increases were observed after culture at 3% O2 and following DFO treatment. We observed significantly higher uptake of 125I-TTR and Alexa-594-TTR when cells were cultured at 1 and 3% O2 and in the presence of 200 μM DFO than at 8 and 21% O2. When JEG-3 choriocarcinoma cells were transfected with TTR promoter reporter constructs, increased luciferase activity was measured in cells cultured at 1 and 3% O2 in comparison to 8 and 21% O2. We conclude that placental TTR expression and uptake is increased by the relative hypoxia observed in the first trimester of pregnancy, a time when materno–fetal T4 transfer is the sole source of fetal T4.
Queensland Health Pathology Service, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia
Department of Endocrinology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia
Department of Obstetrics and Gynaecology, University of Queensland, Brisbane, Queensland 4029, Australia
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Queensland Health Pathology Service, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia
Department of Endocrinology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia
Department of Obstetrics and Gynaecology, University of Queensland, Brisbane, Queensland 4029, Australia
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Queensland Health Pathology Service, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia
Department of Endocrinology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland 4029, Australia
Department of Obstetrics and Gynaecology, University of Queensland, Brisbane, Queensland 4029, Australia
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Verapamil inhibits tri-iodothyronine (T3) efflux from several cell types, suggesting the involvement of multidrug resistance-associated (MDR) proteins in T3 transport. The direct involvement of P-glycoprotein (P-gp) has not, however, been investigated. We compared the transport of 125I-T3 in MDCKII cells that had been transfected with mdr1 cDNA (MDCKII-MDR) versus wild-type MDCKII cells (MDCKII), and examined the effect of conventional (verapamil and nitrendipine) and specific MDR inhibitors (VX 853 and VX 710) on 125I-T3 efflux. We confirmed by Western blotting the enhanced expression of P-gp in MDCKII-MDR cells. The calculated rate of 125I-T3 efflux from MDCKII-MDR cells (around 0.30/min) was increased twofold compared with MDCKII cells (around 0.15/min). Overall, cellular accumulation of 125I-T3 was reduced by 26% in MDCKII-MDR cells compared with MDCKII cells, probably reflecting enhanced export of T3 from MDCKII-MDR cells rather than reduced cellular uptake, as P-gp typically exports substances from cells. Verapamil lowered the rate of 125I-T3 efflux from both MDCKII and MDCKII-MDR cells by 42% and 66% respectively, while nitrendipine reduced 125I-T3 efflux rate by 36% and 48% respectively, suggesting that both substances inhibited other cellular T3 transporters in addition to P-gp. The specific MDR inhibitors VX 853 and VX 710 had no effect of 125I-T3 efflux rate from wild-type MDCKII cells but reduced 125I-T3 export in MDCKII-MDR cells by 50% and 53% respectively. These results have provided the first direct evidence that P-gp exports thyroid hormone from cells.
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Abstract
We have studied the uptake of 125I-thyroxine (125I-T4) in the human choriocarcinoma cell line JAR. Uptake of 125I-T4 was time-dependent, stereospecific and reversible, with a saturable component of 33% after 120 min of incubation. Kinetic analysis of the initial specific uptake rates indicated the presence of a single uptake process with a Michaelis constant of 59·4 ± 13·9 nm (n=12) and maximum velocity of 0·29 ± 0·06 pmol/min per mg protein. Uptake was dependent on intracellular energy as, in the presence of 2 mm potassium cyanide, saturable uptake was reduced to 60·6 ± 8·5% (n=4) of control uptake. Uptake was also temperature-dependent. Saturable 125I-T4 uptake after 60 min of incubation was 26·1 ± 3·0% at 25 °C (n=6) and 27·3 ± 5·7% at 4 °C of control uptake at 37 °C. Ouabain did not inhibit 125I-T4 uptake indicating that the uptake was independent of the Na gradient across the cell membrane. Although T4 uptake was stereospecific, as d-T4 failed to inhibit 125I-l-T4 uptake, it was not specific for T4, as tri-iodothyronine (T3) and reverse T3 also inhibited 125I-T4 uptake. We conclude that JAR cells have a saturable, stereospecific and reversible membrane transport mechanism for T4 which is dependent on intracellular energy, but independent of the Na+ gradient across the cell membrane.
Journal of Endocrinology (1995) 146, 233–238
