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 (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 mu M 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 I-125-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. Journal of Endocrinology (2012) 212, 159-16