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Highlights • IL4Rα is expressed in trophoblast cells in healthy pregnancies, spontaneous miscarriages (SM) and recurrent miscarriages (RM). • IL4Rα is downregulated in the syncytiotrophoblast of SM and of RM. • TLR4 is expressed in trophoblast cells in healthy pregnancies, SM, and RM. • The intermediate villous trophoblast showed a lower expression of TLR4 in SM. Abstract Background The purpose of this study was to analyze the involvement of signaling via Interleukin-4-Receptor α (IL4Rα) and Toll like receptor (TLR) 4 at the fetomaternal interface in the process of early pregnancy. Patients And Methods Placenta specimens of 46 patients in early pregnancy were analyzed (normal pregnancy (n = 15), spontaneous (n = 15) and habitual abortion (n = 16)). TLR4 and IL4Rα were analyzed by immunohistochemistry, immunofluorescence and real time PCR. Statistical analysis was carried out using SPSS 23 and Microsoft Excel. Results IL4Rα could be detected in trophoblast cells of all groups. It was significantly downregulated in the syncytiotrophoblast of spontaneous and recurrent abortions (p = 0.001), and in decidual tissue of spontaneous abortions (p = 0.001). Expression of TLR4 was decreased in the intermediate villous trophoblast (IVT) and decidua of spontaneous abortions (p = 0.04 & 0.003, respectively). On mRNA level expression of IL4Rα and TLR4 was significantly decreased in the group of recurrent miscarriages (IL4Rα p = 0.002, TLR4 p = 0.004). Conclusion This study contributes new findings to the understanding of the complex molecular interplay at the fetomaternal interface in normal pregnancy and miscarriages. For the first time signaling via IL4Rα being involved at the very beginning of the generation of new life could demonstrated. Moreover, new evidence was provided regarding TLR4 playing a pivotal role in early pregnancy. [ABSTRACT FROM AUTHOR]

• There are distinct profiles in epigenetic regulation in recurrent miscarriages (RM) compared to spontaneous miscarriages (SM). • Histone modifications H3K4me3 and H3K9ac are overall reduced in placental tissue of SM. • In recurrent miscarriages particularly H3K9ac is reduced. • Histone modifications differ in the distinct compartments of the placental tissue. • There might be an association to the downregulation of gene activation with the development of miscarriages. In contrast to genetic abnormalities which are well known to be responsible for around 50 % of human miscarriages, there is very few data about epigenetic alterations in spontaneous and recurrent miscarriages (SM, RM). The aim of this study was to analyze the histone modification marks H3K9ac and H3K4me3 in SM and RM. The abundance of histone modifications H3K4me3/H3K9ac was analyzed by western blot in frozen abortion material of SM and RM compared to a control group of legal pregnancy terminations. Further, to characterize placental tissue cells expressing H3K4me3/H3K9ac immunohistochemistry (IHC) and immunofluorescence was performed in 20 SM, 19 RM and 26 controls. The western blot data showed a tendency to an overall reduction of H3K4me3/H3K9ac, in the placental tissue of particularly SM. Further we differentiated between syncytiotrophoblast, cytotrophoblast and decidual cells and found a significant decrease of H3K4me3 in SM in cytotrophoblast cells and syncytial stroma. In RM H3K4me3 was downregulated exclusively in the syncytiotrophoblast. H3K9ac was reduced in SM and RM in all evaluated compartments, except from the syncytiotrophoblast. Our study showed an overall reduced histone modification of H3K4me3 and H3K9ac in the placental tissue of SM. Concerning RM, particularly the reduction of H3K9ac was detected in the placental tissue, indicating that RM group has distinct profile in epigenetic regulation. Whether these histone modifications are part of a possible pathophysiologic cascade during SM and RM or are merely indicating a defective placentation, cannot be concluded from this study. [ABSTRACT FROM AUTHOR]

• Epigenetic changes are involved in placenta of women suffering from PE. • Histone modifications H3K4me3 and H3K9ac are reduced in PE placentas. • Differences were detected gender independently. • H3K4me3 positively correlated with maternal age. Alterations of DNA accessibility and chromatin structure are associated with diseases. We aimed to investigate epigenetic modifications in preeclampsia (PE), a pregnancy-associated hypertonic disease. Specifically, we addressed histone modification proteins H3K9ac (acetylated lysine 9 of the histone H3) and H3K4me3 (trimethylated lysine 4 of the histone H3) in PE. We analyzed expression of histone proteins H3K4me3 and H3K9ac in 32 PE and 32 control placentas by immunohistochemistry. Further, we carried out confirmatory western blot analysis of respective proteins in 6 representative placentas. We then applied regression models with additional adjustment for potential confounders. Expression of H3K4me3 and H3K9ac is reduced in PE placentas as demonstrated by immunohistochemical stainings and western blot. There are no differences between female and male fetuses in the presence of these histone modifications. H3K4me3 positively correlated with maternal age (r = 0.444, p = 0.034). Expression of the placental histone proteins H3K4me3 and H3K9ac is reduced in PE, and independent of fetal gender. Our study underlines the involvement of epigenetic changes in the placenta of women suffering from PE. [ABSTRACT FROM AUTHOR]