Synthesis of Thyroid Hormone Binding Proteins Transthyretin and Albumin by Human Trophoblast

McKinnon, Brett; Li, Huika; Richard, Kerry; Mortimer, Robin H.

doi:10.1210/jc.2005-0696

Cited by 101 publications

(64 citation statements)

References 33 publications

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“…A2mp endoprotease inhibitor and vehicle for different growth factors such as vascular endothetial, placental, and platelet-derived; proposed to have role in regulating the rate at which trophoblast invasion proceeds (13,18) proposed to have predictive and diagnostic value for preeclampsia Afp Alfa-fetoprotein infertility in Afp-KO females due to dysfunction of the hypothalamic/pituitary system and anovulation (7,12,14) protects Ttr Prealbumin, thyroxine-binding, TBPA, PALB plays a role in maternal-fetal thyroid hormone transport and increases at implantation sites (3,8,33,52) produces a receptive endometrium during the luteal phase higher oxidative stress in preeclampsia is major destabilizing factor of functional dimeric TTR form in women mouse model of reproductive failure after a correct implantation, we have identified novel gene changes taking place in failing pregnancies and their potential gene network. Furthermore, these gene expression changes were associated with pregnancy failure.…”

Section: A2mmentioning

confidence: 99%

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites

Nuño-Ayala

Guillén

Arnal

et al. 2012

Physiological Genomics

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mocysteinemia has been reported in human reproduction as a risk factor for early pregnancy loss, preeclampsia, and congenital birth defects like spina bifida. Female infertility was also observed in cystathionine beta synthase-deficient mice (Cbs-KO) as an animal model for severe hyperhomocysteinemia. The aim for the present research was to elucidate the time-point of pregnancy loss and to pinpoint gene and cellular changes involved in the underlying pathological mechanism. By mating 90-dayold wild-type and Cbs-KO female mice with their homologous male partners, we found that pregnancy loss in Cbs-KO occurred between the 8th and 12th gestation day during placenta formation. DNA microarrays were carried out on uterus from implantation and interimplantation samples obtained on day 8. The results allowed us to select genes potentially involved in embryo death; these were individually confirmed by RT-qPCR, and their expressions were also followed throughout pregnancy. We found that changes in expression of Calb1, Ttr, Expi, Inmt, Spink3, Rpgrip1, Krt15, Gzmc, Gzmb, Tdo2, and Afp were important for pregnancy success, since a different regulation in Cbs-KO mice was found. Also, differences in relationships among selected genes were observed, indicating a dysregulation of these genes in Cbs-KO females. In conclusion, our data provide more information on the gene expression cascade and its timely regulated process required for a successful pregnancy. In addition, we unveil new potential avenues to explore further investigations in pregnancy loss.reproduction; hyperhomocysteinemia; uterus IN EPIDEMIOLOGICAL AND META-ANALYSIS studies, hyperhomocysteinemia (Hhcy) has been found to be a risk factor for placentally mediated diseases, such as preeclampsia, spontaneous abortion, and placental abruption (50). In case-control studies, it has been also reported that homocysteine (Hcy) levels are frequently elevated in complicated pregnancies due to preeclampsia or umbilical placental vascular disease over those present in the normal pregnancy group (11,37,54).Hcy is a nonprotein sulfur amino acid and a substrate for cystathionine ␤-synthase (Cbs) in the transsulfuration pathway, which represents its main metabolic fate. Alternatively, Hcy can be converted into methionine through the remethylation pathway. Three metabolic reactions using different methyl donors are known; one uses betaine, and the reaction is catalyzed by betaine-homocysteine methyltransferase, the second one catalyzed by 5-methyltetrahydrofolate-homocysteine methyltransferase uses as donor 5-methyltetrahydrofolate (43), and the third one is catalyzed by S-methylmethionine-homocysteine methyltransferase with methyl donor S-methylmethionine (46). These metabolic pathways are expressed in different tissues during development. Thus, Cbs is expressed in liver, pregnant myometrium, and decidual tissue, whereas methionine synthase is expressed in all embryonic tissues, the liver being the primary site of activity for these enzymes (48,51,58).Cbs-deficient [Cbs knockout...

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Section: A2mmentioning

confidence: 99%

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites

Nuño-Ayala

Guillén

Arnal

et al. 2012

Physiological Genomics

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“…Four different THBGs have been identified in the placenta. 51 Two of these THBGs, namely transthyretin and albumin, have been localized in syncytiotrophoblasts of term placenta, at the subapical region and on the apical membrane surface, respectively. In a study by McKinnon and colleagues, in vitro inhibition of the binding of T 4 to THBGs resulted in increased T 4 deiodination by D3 in placental cytosol, which indicates a possible role for these THBGs in protecting thyroid hormones from metabolism during their transit through trophoblasts.…”

Section: Thyroid-hormone-binding Globulins and Thyroid Hormone Receptorsmentioning

confidence: 99%

The role of the placenta in thyroid hormone delivery to the fetus

2009

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The transplacental passage of thyroid hormones from the maternal circulation to the fetal circulation within the human hemochorial placenta is important for normal fetal development, particularly the development of the central nervous system. The role of maternal thyroid hormones is particularly important in the first half of pregnancy, before the onset of endogenous thyroid hormone production in the fetus. The human placenta regulates the quantity and composition of different forms of transported thyroid hormones to ensure that the requisite levels are present in the fetus for each stage of development. Transplacental thyroid hormone supply to the fetus is modulated by several factors, including the following proteins: plasma membrane transporters, which regulate the passage of thyroid hormones in and out of cells; iodothyronine deiodinases, which metabolize thyroid hormones; and proteins within trophoblast cells, which bind thyroid hormones. In pathological situations of either maternal or fetal thyroid hormone deficiency during pregnancy, the placenta seems to lack the full compensatory mechanisms necessary to optimize maternal-fetal transfer of thyroid hormones. Inadequate passage of thyroid hormones can lead to suboptimal fetal thyroid hormone levels, which might contribute to the neurodevelopmental delay associated with such conditions. Thus, maintaining normal maternal thyroid hormone status is likely to be the primary factor in ensuring adequate transplacental thyroid hormone passage and appropriate iodide supply to the fetus.

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“…Previous work from our group has demonstrated that the human placenta is also capable of producing albumin but not TBG. However, the role of albumin, which has a low affinity but high capacity for thyroid hormone binding, within the placenta is not yet known (McKinnon et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…We have recently reported that human trophoblast cells produce the T 4 and retinol-binding protein, TTR (McKinnon et al 2005). Studies on polarised choriocarcinoma JEG-3 cells maintained in bicameral chambers indicate that TTR is secreted apically and basally (Landers et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Expression and uptake of the thyroxine-binding protein transthyretin is regulated by oxygen in primary trophoblast placental cells

Patel

Landers²,

Mortimer³

et al. 2011

Journal of Endocrinology

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Transplacental delivery of maternal thyroid hormones to the fetus, in particular thyroxine (T 4 ), is critical in ensuring normal fetal neurological development. The fetus relies on maternal T 4 till around 16 weeks gestation, but mechanisms of placental T 4 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% O 2 and 200 mM desferrioxamine (DFO)) for 24 h. We observed sevenfold higher expression of TTR mRNA and protein levels at 1% O 2 than at 8 and 21% O 2 . Significant increases were observed after culture at 3% O 2 and following DFO treatment. We observed significantly higher uptake of 125 I-TTR and Alexa-594-TTR when cells were cultured at 1 and 3% O 2 and in the presence of 200 mM DFO than at 8 and 21% O 2 . When JEG-3 choriocarcinoma cells were transfected with TTR promoter reporter constructs, increased luciferase activity was measured in cells cultured at 1 and 3% O 2 in comparison to 8 and 21% O 2 . 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 T 4 transfer is the sole source of fetal T 4 .

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Synthesis of Thyroid Hormone Binding Proteins Transthyretin and Albumin by Human Trophoblast

Cited by 101 publications

References 33 publications

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites

Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites

The role of the placenta in thyroid hormone delivery to the fetus

Expression and uptake of the thyroxine-binding protein transthyretin is regulated by oxygen in primary trophoblast placental cells

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