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

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.