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 (T4), is critical in ensuring normal fetal neurological development. The fetus relies on maternal T4till around 16 weeks gestation, but mechanisms of placental T4transport 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% O2and 200 μM desferrioxamine (DFO)) for 24 h. We observed sevenfold higher expression ofTTRmRNA and protein levels at 1% O2than at 8 and 21% O2. Significant increases were observed after culture at 3% O2and following DFO treatment. We observed significantly higher uptake of125I-TTR and Alexa-594-TTR when cells were cultured at 1 and 3% O2and 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% O2in 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 T4transfer is the sole source of fetal T4.