Abstract
Oxidative stress (OS)-induced senescence of the amniochorion has been associated with parturition at term. We investigated whether telomere fragments shed into the amniotic fluid (AF) correlated with labor status and tested if exogenous telomere fragments (T-oligos) could induce human and murine amnion cell senescence. In a cross-sectional clinical study, AF telomere fragment concentrations quantitated by a validated real-time PCR assay were higher in women in labor at term compared to those not in labor. In vitro treatment of primary human amnion epithelial cells with 40 μM T-oligos ([TTAGGG]2) that mimic telomere fragments, activated p38MAPK, produced senescence-associated (SA) β-gal staining and increased interleukin (IL)-6 and IL-8 production compared to cells treated with complementary DNA sequences (Cont-oligos, [AATCCC]2). T-oligos injected into the uteri of pregnant CD1 mice on day 14 of gestation, led to increased p38MAPK, SA-β-gal (SA β-gal) staining in murine amniotic sacs and higher AF IL-8 levels on day 18, compared to saline treated controls. In summary, term labor AF samples had higher telomere fragments than term not in labor AF. In vitro and in situ telomere fragments increased human and murine amnion p38MAPK, senescence and inflammatory cytokines. We propose that telomere fragments released from senescent fetal cells are indicative of fetal cell aging. Based on our data, these telomere fragments cause oxidative stress associated damages to the term amniotic sac and force them to release other DAMPS, which, in turn, provide a sterile immune response that may be one of the many inflammatory signals required to initiate parturition at term.
Highlights
Signals that initiate normal labor are still unclear [1] multitudes of putative biochemical mediators and their pathways have been suggested as initiators [2,3]
We used samples that are gestational age matched to assure that the effect we report in this study are not impacted by gestational age differences
Telomere fragments are not cytotoxic to human amniotic epithelial cell cultures Concentrations of telomere fragments circulating in amniotic fluid (AF) are higher under conditions that we previously documented to be associated with increased Oxidative stress (OS) and short cellular telomeres, term labor [13,14]
Summary
Signals that initiate normal labor are still unclear [1] multitudes of putative biochemical mediators and their pathways have been suggested as initiators [2,3]. The best documented signals occur in both maternal and fetal compartments and include endocrine (Corticotrophin relasing hormone [CRH], Adrenocorticotropic hormone [ACTH], functional progesterone withdrawal), immune (leukocyte and leukotriene activation) and mechanical factors Telomere Fragments Induce Amnion Cell Senescence uterine stretching and amniochorionic membrane disruption). These factors cause an inflammatory activation (mostly mediated by cytokines), and prostaglandin production to transform a quiescent myometrium to an active contractile state at term [2,4,5,6,7,8]. Pathological activation of myometrial contractility by cytokines and prostaglandins has been implicated in spontaneous preterm birth (PTB) [9,10,11]. Identification of the critical signals and understanding their molecular mechanisms that initiate parturition is essential for reducing the risk of PTB, a major pregnancy complication
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