Telomere Length and Global DNA Methylation in Pregnancy Loss

Background:Telomere and DNA methylation play a key role in several complex pathologies. Telomeres protect chromosome and genomic integrity and DNA methylation influences gene expression both playing a fundamental role in the cell cycle regulation being indicators of cellular health and age. Methylation of subtelomeric regions is closely related to telomere length, being highly rich in CpG isles both involved and fundamental in the regulation of embryonic development and fertility.Aim:The aim of this study is to evaluate whether a correlation between telomere length and global DNA methylation may predict and contribute to the risk of early pregnancy loss (EPL). Materials and Methods:In a case control study including spontaneous pregnancy loss cases (EPL, n=92) and women who voluntarily decided to terminate pregnancy (VPI, n=87), telomere length, indicated as T/S, and LINE-1 methylation, evaluated as a surrogate for global DNA methylation, have been assessed and results statistically computed. Results:EPL had significantly lower mean T/S values when compared to VPI subgroup (T/SEPL 323.4±134.8 vs T/SVPI 425.8±268.24; P= 0.00014). Similarly, LINE-1 mean methylation level was significantly lower in EPL (EPL 82.04±3.63 vs VPI 85.28±3.44; P<0.0001). Considering that telomeres length is an indicator of the biological aging, we decided to verify if T/S differently varied in relation to age in the two subgroups. After correlation analysis, we found a comparable lowering rate in the two subgroups (Pslope=0.8958) and a significantly different Y-axis intercept ascribing to the EPL subgroup a higher lowering (EPLr2=0.0001587 vs VPIr2=0.0005965; Pintercept=0.0019). In order to found out if telomere length changing differently linked to global DNA methylation levels, we correlated T/S and LINE-1 values and found a significant difference ascribing to the EPL subgroup a stronger dependence (EPLr2 = 0.004759 vs VPIr2 =0.001896; Pintercept<0.0001).Conclusions:This study offers a valuable multi-level strategy to investigate epigenetic fluctuations associated with pregnancy loss and highlights how both hypomethylation and telomere attrition could be involved in the etiopathogenesis of early miscarriage. Altogether, these results can serve as possible prognostic markers and to identify novel targets for future innovative epidrugs.