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

Abstract

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 μM 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 μM 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 .