The role of Thyroid hormone Transporters Monocarboxylate Transporter 10 (MCT10) and Monocarboxylate Transporter 8 (MCT8) in extravillous trophoblasts.

Abstract

Thyroid hormones (TH) are important for fetal and placental development. Monocarboxylate transporters 8 and 10 (MCT8, MCT10) are effective plasma membrane TH transporters expressed in the human placenta from 6 weeks of gestation. Both have been localized to human villous trophoblasts and extravillous trophoblasts (EVTs). Aims: Using HTR-8/SVneo cells as a model of 1st trimester EVTs, we assessed 1) Triiodothyronine (T3) effects on gene expression and cell proliferation; 2) the effect of altered MCT8 or MCT10 expression on proliferation and apoptosis; and whether effects were T3-mediated. Methods: 1) Cell proliferation was assessed by the MTT assay at 24-96hrs. Gene expression was assessed by quantitative QPCR (2-48h). 2) MCT8 was down-regulated using siRNA, and MCT8 and MCT10 were over-expressed by plasmid transfection. Effects of altering expression were assessed by MTT assay (Proliferation) and Caspase3/7 activity (Apoptosis). Results: We observed that T3 treatment did not affect HTR-8/SVneo proliferation nor alter the mRNA expressions of TH responsive gene, Connexin43 (Cx43) and the pre-receptor regulators of T3 action, deiodinases 2 and 3 (D2, D3), nor its own transporters, MCT8 and MCT10. However, T3 treatment was observed to decrease the expression of TH receptor β1 (TRβ1) (ANOVA p<0.05). Over-expression of MCT8 or MCT10 reduced cell proliferation by 36% and 29% respectively (ANOVA p<0.05) in the presence of T3. Apoptosis was reduced, independently of T3 treatment, by 24 and 31% (+/- T3 respectively) following overexpression of MCT8, and by 12 and 19% (+/- T3 respectively) following overexpression of MCT10, respectively (ANOVA p<0.005). Conversely, down-regulation of MCT8 resulted in increased apoptosis independently of T3 (p<0.003). Conclusions: HTR-8/SVneo cell proliferation does not change with T3 treatment. In addition, MCT8 and MCT10 may have both T3-dependent (suppress proliferation) and T3-independent (apoptosis) effects in EVTs. This suggests an important role for MCT8 and MCT10 in human placental development.