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The in Vitro Effects of Triiodothyronine on Epidermal Growth Factor-Induced Trophoblast Function

Divisions of Reproductive and Child Health (K.J.B., M.D.K.) and Medical Sciences (C.J.M., F.L.K., J.A.F.), The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Department of Biochemistry and Immunology (G.S.J.W.), St. George’s Hospital Medical School, London SW17 0RE, United Kingdom; and School of Clinical and Laboratory Science (J.N.B.), University of Newcastle, Newcastle upon Tyne NE1 4LP, United Kingdom

Address all correspondence and requests for reprints to: Professor Mark Kilby, Department of Maternal and Fetal Medicine, Division of Reproductive and Child Health, 3rd Floor, Birmingham Women’s Hospital, Edgbaston, Birmingham B15 2TG, United Kingdom. E-mail: m.d.kilby{at}bham.ac.uk.

The development of the human placenta involves a complex process of tightly regulated proliferation and invasion by extravillous trophoblast into the uterine decidua. Inadequate placentation is a feature of intrauterine growth restriction and other gestational pathology. There is some evidence that T₃ plays a role in the regulation of these processes and that T₃ may act synergistically with epidermal growth factor (EGF). The aim of this study was to define the expression of thyroid hormone receptors in extravillous trophoblast, elucidate the effects of T₃ on both proliferation and differentiation of human trophoblast cells of varying origins, and define the potential interaction between EGF and T₃ on these processes. Using immunohistochemistry, specific thyroid hormone receptor isoforms were localized in extravillous trophoblast in first- and second-trimester placental bed biopsies, indicating potential sensitivity to T₃. In studies of human trophoblast-derived cell lines and primary cultures of cytotrophoblast cells in vitro, T₃ and EGF exerted an antiproliferative effect on an extravillous-like cell line (SGHPL-4) but stimulated proliferation in JEG-3 choriocarcinoma cells. EGF enhanced survival of nonproliferative term primary cytotrophoblast cells and significantly enhanced invasion of fibrin gels by SGHPL-4 cells, an effect attenuated by T₃. Both T₃ and EGF also significantly enhanced SGHPL-4 motility. These results suggest that EGF and T₃ may act synergistically to regulate both proliferation and differentiated function of human trophoblast.

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