Cell Type- and Sex-Specific Dysregulation of Thyroid Hormone Receptors in Placentas in Gestational Diabetes Mellitus

Julia Knabl,Stefan Hutter,Udo Jeschke,Julia Jückstock,Franz Kainer,Sven Mahner,Gernot Desoye,Rebecca Hüttenbrenner,Lena De Maiziere

doi:10.3390/ijms21114056

Abstract

Thyroid hormones are essential for development of trophoblasts and the fetus. They also regulate a wide range of metabolic processes. We investigated the influence of maternal gestational diabetes mellitus (GDM) on thyroid hormone receptor (THR) isoforms THRα1, THRα2, THRβ1 and THRβ2 of the human placenta in a sex- and cell-type specific manner. Term placental tissue was obtained from women with (n = 40) or without GDM (control; n = 40). THRs levels were measured by semi-quantitative immunohistochemistry and real-time qRT-PCR. We localized THR immunostaining in syncytiotrophoblast (SCT), which was the tissue with the strongest signal. Double immunofluorescence identified THR in decidual cells in the stroma and in extravillous cytotrophoblasts. GDM did not change THRα1 immunolabelling intensity in decidua, but was associated with a stronger immunolabelling in SCT compared to GDM (p < 0.05). The SCT difference of GDM vs. control was strongest (p < 0.01) in female placentas. THRα2 was only weakly present and immunolabelling was weaker (p < 0.05) in SCT of only male GDM placentas in comparison to male controls. THRβ1/β2 immunostaining was weak in all cell types without changes in GDM. However, more THRβ1/2 protein was present (p < 0.001) in male than female placentas. All these protein changes were paralleled by changes of THR transcript levels. The data show that THR are expressed in term trophoblast in relation to fetal sex. Maternal GDM influences predominantly THRα1 in SCT, with the strongest GDM effect in SCT of female placentas.

Highlights

Thyroid hormones are involved in the regulation of major metabolic and cellular processes including gluconeogenesis, lipogenesis, cell proliferation, apoptosis and cell immunity
We investigated the influence of maternal gestational diabetes mellitus (GDM) on thyroid hormone receptor (THR) isoforms THRα1, THRα2, THRβ1 and THRβ2 of the human placenta in a sex- and cell-type specific manner
We found differences in immunoreactivity for the various receptor isoforms, which were affected by GDM, if at all, in a cell type and fetal sex-specific manner

Summary

Introduction

Thyroid hormones are involved in the regulation of major metabolic and cellular processes including gluconeogenesis, lipogenesis, cell proliferation, apoptosis and cell immunity. The hormone Triiodothyronine (T3) is the high-affinity ligand of thyroid hormone receptors (THRs). THRs belong to the superfamily of nuclear receptors and are Type II steroid hormone receptors. Type I steroid hormone receptors, they are located in the nucleus and form heterodimers with the retinoid X receptor (RXR) to bind to thyroid hormone response elements (TREs). THRA (NR1A1) and THRB (NR1A2), encode the isoforms THRα and THRβ, which code for the four ligand-binding thyroid receptors THRα1, THRβ1, THRβ2 and THRβ3 and the four non-ligand binding receptors THRα2, THR∆α1, THR∆β2 and THR∆β3, which are alternative splice variants [2,3]

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