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

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.

Subsequent perinatal outcomes of pregnancy with two consecutive pregnancies with gestational diabetes mellitus: A population‐based cohort study

“…A previous study reported that maternal GDM exerts effect on the human placental thyroid hormone receptor (THR) subtypes THRα1, THRα2, THRβ1, and THRβ2. 22 We speculate that this effect may be persistent if a woman with GDM became pregnant again. The association between thyroid autoimmunity and spontaneous type 1 diabetes has been well established by numerous studies.…”

“…In the present study, the incidences of thyroid disorders and thyroiditis were higher in subsequent pregnancies ( p = .003 and p = .005). A previous study reported that maternal GDM exerts effect on the human placental thyroid hormone receptor (THR) subtypes THRα1, THRα2, THRβ1, and THRβ2 22 . We speculate that this effect may be persistent if a woman with GDM became pregnant again.…”

Biological networks in gestational diabetes mellitus: insights into the mechanism of crosstalk between long non-coding RNA and N6-methyladenine modification

“…Genes in the subnetwork were enriched in certain hormone signaling pathways, including thyroid hormone and oxytocin (OT). Recent evidence indicates that perturbations of the thyroid hormone signaling pathway and antibodies are associated with GDM development and mal-outcome [ 49 , 51 ]. Emerging evidence suggests a role of OT in the pathogenesis of insulin resistance, obesity, and dyslipidemia [ 52 , 53 ], which are hallmarks or risk factors for GDM.…”

N6-Methyladenosine-Related Gene Signature Associated With Monocyte Infiltration Is Clinically Significant in Gestational Diabetes Mellitus

“…Recent studies have revealed that a small but significant population of patients with GDM develop postpartum T1DM (52,53). Emerging evidence suggests that perturbations of the thyroid hormone signaling pathway and antibodies are associated with GDM development and adverse outcomes (54,55). In terms of the GO biological process category, the DMRGs were closely related to inflammatory-and immune-related biological processes.…”