Telomere-Related Disorders in Fetal Membranes Associated With Birth and Adverse Pregnancy Outcomes

Abstract

Telomere disorders have been associated with aging-related diseases, including diabetes, vascular, and neurodegenerative diseases. The main consequence of altered telomere is the induction of the state of irreversible cell cycle arrest. Though several mechanisms responsible for the activation of senescence have been identified, it is still unclear how a cell is indeed induced to become irreversibly arrested. Most tissues in the body will experience senescence throughout its lifespan, but intrinsic and extrinsic stressors, such as chemicals, pollution, oxidative stress (OS), and inflammation accelerate the process. Pregnancy is a state of OS, as the higher metabolic demand of the growing fetus results in increased reactive oxygen species production. As a temporary organ in the mother, senescence in fetal membranes and placenta is expected and linked to term parturition (>37 weeks of gestation). However, a persistent, overwhelming, or premature OS affects placental antioxidant capacity, with consequent accumulation of OS causing damage to lipids, proteins, and DNA in the placental tissues. Therefore, senescence and its main inducer, telomere length (TL) reduction, have been associated with pregnancy complications, including stillbirth, preeclampsia, intrauterine growth restriction, and prematurity. Fetal membranes have a notable role in preterm births, which continue to be a major health issue associated with increased risk of neo and perinatal adverse outcomes and/or predisposition to disease in later life; however, the ability to mediate a delay in parturition during such cases is limited, because the pathophysiology of preterm births and physiological mechanisms of term births are not yet fully elucidated. Here, we review the current knowledge regarding the regulation of telomere-related senescence mechanisms in fetal membranes, highlighting the role of inflammation, methylation, and telomerase activity. Moreover, we present the evidences of TL reduction and senescence in gestational tissues by the time of term parturition. In conclusion, we verified that telomere regulation in fetal membranes requires a more complete understanding, in order to support the development of successful effective interventions of the molecular mechanisms that triggers parturition, including telomere signals, which may vary throughout placental tissues.

Associations of Maternal Polyunsaturated Fatty Acids With Telomere Length in the Cord Blood and Placenta in Chinese Population

“…This suggests that the mechanisms by which n-3 PUFAs affect TL may reside in both their functions in epigenetic modification and their anti-inflammatory or anti-oxidative stress effects (27)(28)(29). To note, no significant associations of the TERT promoter methylation with TL in the placenta were found in our study, indicating that TL in the placenta might be primarily influenced by inflammation or oxidation instead of the TERT methylation and associated telomerase activity, which are in higher levels in late pregnancy (56). Still, no associations between maternal DHA and total n-3 PUFAs and the TERT promoter methylation were found herein, indicating that the effects of maternal n-3 PUFAs on placenta TL may depend on their regulatory roles in inflammation or metabolic processes (63), rather than their functions in epigenetic modifications.…”

“…In comparison with the cord blood cells that are at early hematopoiesis and abundant in telomerase-expressing stem cells, placenta cells undergo cellular senescence such that they may have shortened TL (17). As the pregnancy progresses, telomerase activity in the placenta declines, resulting in shortened TL across gestation with the shortest telomeres at term (54,55), probably due to the increasing production of mediators, particularly pro-inflammatory cytokines, neutrophil recruitment chemokines, and arachidonic acid metabolites of chorioamniotic cells in the third trimester of pregnancy (56). However, few studies indicate a discrepancy in the results of TL in the cord blood compared to the placenta (19,57), and we found no differences in TL between the cord blood and the placenta in the current study.…”

Dysregulated non-coding telomerase RNA component and associated exonuclease XRN1 in leucocytes from women developing preeclampsia-possible link to enhanced senescence

“…Telomerase activity and cell senescence are altered during pregnancy and delivery since the placenta/fetal membranes are unique to this context, and there is evidence that the timing of these mechanisms may be temporally related to the timing of parturition 1 , 2 , 23 . There is also data to suggest that telomere-related cellular aging may be associated with PE, with premature activation of this pathway leading to placental villous telomere shortening, telomere aggregates, and trophoblast dysfunction in PE placentas 5 , 24 – 26 .…”

“…Pregnancy is a state of oxidative stress as the higher metabolic demand of the growing fetus results in increased reactive oxygen species production 1 , 2 . Oxidative stress is implicated in the pathophysiology of many reproductive complications including infertility, miscarriage and pre-eclampsia (PE), but the mechanisms of these complications are not fully elucidated.…”

Telomere Length in Chromosomally Normal and Abnormal Miscarriages and Ongoing Pregnancies and Its Association with 5-hydroxymethylcytosine Patterns

“…However, normal telomerase expression and activity in placental tissues is too low to maintain telomere homeostasis for the entire gestation period. The alternative mechanism of telomere elongation–ALT–which is based on recombination, has not been directly observed in gestational tissues [ 46 ]. Nevertheless, in first-trimester trophoblasts, a higher TERRA expression than in matched somatic cells from cord blood coincides with extremely low telomerase levels, suggesting a possible ALT role [ 47 ].…”