Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis

Perinatal maternal alcohol consumption and methylation of the dopamine receptor DRD4 in the offspring: the Triple B study

Maternal alcohol use during the perinatal period is a major public health issue, the higher ends of which are associated with foetal alcohol spectrum disorder and a range of adverse health outcomes in the progeny. The underlying molecular mechanisms remain largely unknown but may include the epigenetic disruption of gene activity during development. Alcohol directly activates the neurotransmitter dopamine, which plays an essential role in neurodevelopment. To investigate whether antenatal and early postnatal alcohol consumption were associated with differential dopamine receptor DRD4 promoter methylation in infants (n = 844). Data were drawn from the large population based Triple B pregnancy cohort study, with detailed information on maternal alcohol consumption in each trimester of pregnancy and early postpartum. DNA was extracted from infant buccal swabs collected at 8-weeks. DRD4 promoter DNA methylation was analysed by Sequenom MassARRAY. No strong evidence was found for an association between alcohol consumption during pregnancy and infant DRD4 methylation at 8-weeks postpartum. However, maternal alcohol consumption assessed contemporaneously at 8-weeks postpartum was associated with increased methylation at 13 of 19 CpG units examined (largest Δ + 3.20%, 95%Confidence Interval:1.66,4.75%, P =  0.0001 at CpG.6). This association was strongest in women who breastfeed, suggesting the possibility of a direct effect of alcohol exposure via breast milk. The findings of this study could influence public health guidelines around alcohol consumption for breastfeeding mothers; however, further research is required to confirm these novel findings

DNA methylation as a predictor of fetal alcohol spectrum disorder

Abstract Background Fetal alcohol spectrum disorder (FASD) is a developmental disorder that manifests through a range of cognitive, adaptive, physiological, and neurobiological deficits resulting from prenatal alcohol exposure. Although the North American prevalence is currently estimated at 2–5%, FASD has proven difficult to identify in the absence of the overt physical features characteristic of fetal alcohol syndrome. As interventions may have the greatest impact at an early age, accurate biomarkers are needed to identify children at risk for FASD. Building on our previous work identifying distinct DNA methylation patterns in children and adolescents with FASD, we have attempted to validate these associations in a different clinical cohort and to use our DNA methylation signature to develop a possible epigenetic predictor of FASD. Methods Genome-wide DNA methylation patterns were analyzed using the Illumina HumanMethylation450 array in the buccal epithelial cells of a cohort of 48 individuals aged 3.5–18 (24 FASD cases, 24 controls). The DNA methylation predictor of FASD was built using a stochastic gradient boosting model on our previously published dataset FASD cases and controls (GSE80261). The predictor was tested on the current dataset and an independent dataset of 48 autism spectrum disorder cases and 48 controls (GSE50759). Results We validated findings from our previous study that identified a DNA methylation signature of FASD, replicating the altered DNA methylation levels of 161/648 CpGs in this independent cohort, which may represent a robust signature of FASD in the epigenome. We also generated a predictive model of FASD using machine learning in a subset of our previously published cohort of 179 samples (83 FASD cases, 96 controls), which was tested in this novel cohort of 48 samples and resulted in a moderately accurate predictor of FASD status. Upon testing the algorithm in an independent cohort of individuals with autism spectrum disorder, we did not detect any bias towards autism, sex, age, or ethnicity. Conclusion These findings further support the association of FASD with distinct DNA methylation patterns, while providing a possible entry point towards the development of epigenetic biomarkers of FASD