Differential Triiodothyronine Responsiveness and Transport by Human Cytotrophoblasts from Normal and Growth-Restricted Pregnancies

Context: Abnormal placentation in human pregnancy is associated with intrauterine fetal growth restriction (IUGR). Our group has previously reported the association between severe IUGR, lower fetal circulating concentrations of thyroid hormones (THs), and altered expression of TH receptors and TH transporters within human placental villi. We postulate that altered TH bioavailability to trophoblasts may contribute to the pathogenesis of IUGR. Design and Objective: Cytotrophoblasts were isolated from normal and IUGR human placentae to compare their responsiveness to T3 and their capability for T3 transport. Results: Compared with normal cytotrophoblasts, the viability of IUGR cytotrophoblasts (assessed by methyltetrazoleum assay) was significantly reduced (P <0.001), whereas apoptosis (assessed using caspase 3/7 activity and M30 immunoreactivity) was significantly increased after T3 treatment for 48 h (P <0.001 and P <0.01, respectively). The secretion of human chorionic gonadotropin was significantly increased by IUGR cytotrophoblasts compared with normal cytotrophoblasts (P <0.001), independently of T3 treatment. Net transport of [(125)I]T3 was 20% higher by IUGR cytotrophoblasts compared with normal cytotrophoblasts (P <0.001), and this was accompanied by a 2-fold increase in the protein expression of the TH transporter, monocarboxylate transporter 8, as assessed by Western immunoblotting (P <0.01). Conclusions: IUGR cytotrophoblasts demonstrate altered responsiveness to T3 with significant effects on cell survival and apoptosis compared with normal cytotrophoblasts. Increased monocarboxylate transporter 8 expression and intracellular T3 accumulation may contribute to the altered T3 responsiveness of IUGR cytotrophoblasts.