GDM Alters Expression of Placental Estrogen Receptor in a Cell Type and Gender-Specific Manner

Objective: The nuclear receptor estrogen receptor (ER) is one of the key players in energy balance, insulin resistance, and trophoblast differentiation. We tested the hypothesis that gestational diabetes mellitus (GDM) alters expression of placental ER in a cell type-specific manner and that this regulation may involve epigenetic changes. Study Design: Expression of ER was analyzed by immunohistochemistry using the semiquantitative immunoreactive score in 80 placentas (40 GDM/40 controls). Quantitative real-time polymerase chain reaction (PCR) measured ER messenger RNA (mRNA) in decidual tissue. Methylation-specific PCR was performed to analyze cytosine-phosphatidyl-guanine-island methylation of the ER promoter. Results: Expression of ER protein is upregulated (P = .011) in GDM in extravillous trophoblasts but not in syncytiotrophoblast. Gestational diabetes mellitus downregulated ER in decidual vessels only in pregnancies with male but not female fetuses. Furthermore, mRNA of the ER encoding gene estrogen receptor gene 1 (ESR1) was increased (+1.77 fold) in GDM decidua when compared to controls (P = .024). In parallel, the promoter of ESR1 was methylated only in decidua of healthy control individuals but not in GDM. Conclusion: Gestational diabetes mellitus affects expression of placental ER in a cell type-dependent way, on epigenetic level. These data link GDM with epigenetic deregulations of ER expression and open new insights into the intrauterine programming hypothesis of GDM.