Thyroid hormones are essential for optimum fetal neurodevelopment. In-utero nutrition is dependant on adequate placentation. Epidermal growth factor (EGF) and hepatocyte growth factor (HGF) have been demonstrated to affect proliferation of human trophoblast and may therefore play a role in adequate human placentation. Intrauterine growth restriction (a process associated with malplacentation) is associated with fetal hypothyroxinemia and enhanced thyroid receptor (TR) expression on villous trophoblast. As endovascular trophoblast in placental bed biopsies demonstrate the presence of TRs, human trophoblast may be thyroid-responsive. We therefore determined the effects on proliferation and invasion of these cytokines in-vitro and in combination with triiodothyronine (T3) using human villous cytotrophoblast cultures, JEG-3 choriocarcinoma cells and the extravillous trophoblast-like cell line SGHPL-4. In JEG-3 cells, HGF-induced a significant anti-proliferative effect (p<0.001) when cultured in 10% charcoal stripped FCS, which was attenuated in 0.5% FCS. T3 was significantly pro-proliferative in stripped media (p<0.001) and anti-proliferative in 0.5% FCS (p<0.001). EGF alone was pro-proliferative when cultured in stripped medium (p<0.05). In primary cultures of term cytotrophoblast (n=4), which do not proliferate in-vitro, EGF significantly enhanced cell survival in both stripped and reduced serum (p<0.001), HGF treatment decreased cell survival in 0.5% FCS (p<0.05), and co-culture with T3 had no significant effect. In SGHPL-4 cells, EGF, HGF and T3 (1-100 nM) were all anti-proliferative in 0.5% FCS (p<0.001), but this effect was attenuated in charcoal stripped FCS. However the co-incubation of T3 with EGF or HGF in each cell line had no effect on proliferation, but significantly increased mRNA encoding malic acid and connexin 45. Using the invasive SGHPL-4 cell line, EGF enhanced invasion into matrigel (P<0.05), which was inhibited in the presence of 10nM T3 (P<0.05). Conclusions: Cytokine-induced proliferative alterations in villous trophoblast and proliferative / invasive effects in extravillous trophoblast are affected by the local presence of T3.
22 - 24 Mar 2004
British Endocrine Societies