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Telomere homeostasis in IUGR placentas – A review
Placenta 39 (2016) 21e23
Contents lists available at ScienceDirect
Placenta journal homepage: www.elsevier.com/locate/placenta
Telomere homeostasis in IUGR placentas e A review Tal Biron-Shental a, b, *, Dana Sadeh-Mestechkin a, b, Aliza Amiel a, b a b
Department of Maternal-Fetal Medicine, Meir Medical Center, Kfar Saba, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 May 2015 Received in revised form 13 November 2015 Accepted 18 November 2015
Telomeres are nucleoprotein structures located at the termini of chromosomes. They are essential for chromosome stability. Telomeres become shorter due to mitotic cycles and environmental factors. When telomeres are shortened and therefore dysfunctional, cellular senescence occurs and organ dysfunction might develop. During pregnancy, fetal growth restriction secondary to placental insufficiency has been linked to impaired telomere homeostasis in which telomeres are shorter, telomerase is decreased, and compensatory mechanisms of telomere capture are enhanced. These characteristics, along with increased signs of senescence, indicate telomere dysfunction in trophoblasts from placentas affected by intrauterine growth restriction (IUGR). This review summarizes the information currently available regarding telomere homeostasis in trophoblasts from human pregnancies affected by IUGR. Improved understanding of placental physiology might help in the development of treatment options for fetuses with IUGR. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Placenta Trophoblasts IUGR Telomeres
1. Telomeres Telomeres are nucleoprotein structures consisting of 5e15 kilobase pairs of repetitive DNA sequences, located at the termini of chromosomes [1]. They are essential for chromosome stability and cell survival, and protect the chromosomes from end-to-end fusion and degradation [2e5]. Telomeres become progressively shorter with each mitotic cycle. They are also shortened by environmental factors, such as oxidative stress [1,2,5e9]. Short telomeres promote cell cycle arrest, apoptosis, and genomic instability [2,6,7]. Once telomeres reach a critically short length, cell senescence is triggered, leading to a process of tissue aging [2,6,7,10]. Dysfunctional telomeres also tend to fuse end-to-end, forming aggregates, irrespective of their length [2]. Telomere length is regulated by telomere-associated proteins; primarily the telomerase enzyme, which adds telomeric repeats to the ends of chromosomes [2,6,11]. Human telomerase reverse transcriptase (hTERT) is the catalytic component of telomerase, and is considered the rate-limiting factor in telomerase activity. A lack of telomerase in normal human cells leads to a progressive decrease in telomere length, resulting in cell senescence and tissue dysfunction [2,6,10,11].
* Corresponding author. Department of Obstetrics and Gynecology, Meir Medical Center, 59 Tschernihovsky, Kfar Saba 44282, Israel. E-mail address: [email protected] (T. Biron-Shental). http://dx.doi.org/10.1016/j.placenta.2015.11.006 0143-4004/© 2016 Elsevier Ltd. All rights reserved.
One component of telomerase, which serves as the RNA template for the addition of telomeric repeats, is encoded by the telomerase RNA component gene (TERC). TERC encodes telomerase and is located at the human chromosome band 3q26. Amplification of this gene is correlated with increased telomeric repeats that prevent telomere shortening and cellular senescence [12]. Senescence is an arrest of cellular proliferation and is involved in the biological process of tissue aging. It is driven by cell division, as well as by oxidative stress, DNA damage and repair response, inflammation, and telomere shortening. Nuclei in senescent human cells are often granulated, containing senescence-associated heterochromatin foci (SAHF) [1,13,14]. When telomeres become critically short, repair pathways are recruited. One such pathway is telomere capture, through which a short telomere acquires a new telomere sequence from a sister chromatid or from another chromosomal end [1]. Telomere length has been studied primarily as a general risk factor for age-related, chronic diseases such as type II diabetes, cardiovascular diseases and malignancies [15e18]. The length of telomeres in leukocytes is inversely related to the risk of developing cancer, diabetes and cardiovascular disease [19]. Shortened and therefore dysfunctional telomeres may cause organ damage and early aging, which consequently lead to diseases. These data also suggest that telomere homeostasis may play a role in human trophoblasts [15e19], as one of the mechanisms underlying placental pathologies.
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2. Intrauterine growth restriction (IUGR) The most common definition of IUGR refers to fetuses with an estimated weight below the 10th percentile for gestational age [21,22]. IUGR can be related to a combination of maternal, fetal, and placenta factors. The most common etiology is abnormal placentation, which results in poor placental perfusion (i.e., placental insufficiency) with subsequent effects on the fetus [21,23]. IUGR increases the risk of intrauterine fetal death, and neonatal morbidity and mortality. Intrauterine insults can cause permanent structural and functional changes to the fetus, which may disrupt postnatal development and increase morbidity and mortality [27,28]. Long-term effects of placental insult persist into adulthood, and include type 2 diabetes mellitus, coronary artery disease, stroke and the metabolic syndrome [24,25,29e32]. Morphometric and microscopic differences are evident between normal placentas and those associated with IUGR. Gross findings in IUGR placentas include low placental weight, thin umbilical cord and parenchymal loss (infarcts). Histological changes also reflect chronic placental ischemia due to maternal or fetal blood supply abnormalities and protein synthesis inhibition, secondary to endoplasmic reticulum stress [26]. This review focuses on telomere homeostasis in placentas from pregnancies complicated with IUGR due to placental insufficiency.
gene copy. TERC serves as the RNA template for the addition of telomeric repeats [36]. Comparison of the number of copies of the TERC gene between IUGR and control placentas at the same gestational age revealed fewer copies of TERC in IUGR placentas, yet these results were not replicated by other research [34]. Toutain et al. used cultured villi obtained from late chorionic villus samples. Patients with severe IUGR (below the third percentile) and controls undergoing prenatal diagnosis for other indications underwent invasive prenatal diagnosis. Quantitative-PCR revealed shorter mean telomere length in the IUGR pregnancies, but no difference in the number of TERC copies. These results may be explained by the timing of placental sampling (early during pregnancy versus the placenta at birth), as well as the small number of samples studied [36]. 6. Telomere aggregates and IUGR An increased number of aggregates were found in preeclampsia (PE), which is also associated with placental insufficiency and short telomeres [2]. Trophoblasts from IUGR placentas tended to have more aggregates compared to controls [12], but the difference was not statistically significant. Another study found no difference in the percentage of aggregates between IUGR and control placentas [2]. The different results from women with or IUGR may reflect variations in the pathophysiology of these two conditions [2].
3. Telomere length and IUGR 7. Senescence and IUGR IUGR can be caused by placental insufficiency, which in some cases may be related to oxidative stress and to intrauterine hypoxia. As noted, telomere length is also influenced by these factors. It has been previously shown that oxidative stress leads to telomere shortening in cultured cells. These observations raised the question of telomere length in IUGR placentas [12]. Several studies have shown that telomeres in placental trophoblasts of pregnancies complicated with IUGR are shorter than uncomplicated pregnancies [1,2,12,33e36]. Davy et al. analyzed telomers length in IUGR (defined as birth weight below 5%) and control placentas. Using Southern blot analysis they found a shorter telomere length in IUGR placentas. Similar results were shown by Biron et al. (IUGR defined as birth weight below 10%), using quantitative FISH [2,12]. These telomere lengths were measured on placentas collected at deliveries from pregnancies complicated by IUGR secondary to placental insufficiency. The results are consistent with observations from a study performed by Toutain at al. They analyzed telomere length on villi obtained from late (chorionic villous sampling) CVS in pregnancies with severe IUGR [34]. Interestingly, no difference in telomere length was found in cord blood leukocytes taken from IUGR and control pregnancies [35], suggesting that the cause may be different, or that different mechanisms, regulate telomere length in fetal blood and in the placenta [12]. 4. Human telomerase reverse transcriptase (hTERT) and IUGR Telomerase activity is suppressed in IUGR placentas compared to placentas from healthy controls at the same gestational age [31]. The level of human telomerase reverse transcriptase (hTERT), the catalytic unit of telomerase, corresponds to telomere elongation. Decreased hTERT expression in IUGR placentas suggests that lower telomerase activity short telomeres in these placentas [12]. 5. Telomerase RNA component gene (TERC) and IUGR The mechanism of telomere shortening in placental dysfunction is not well understood. One possible explanation is decreased TERC
The relationship between cellular senescence and telomere shortening is well-established [1,7,13,14]. Since factors such as oxidative stress and hypoxia, which are known as senescence accelerators, may cause placental damage and IUGR, senescence may be associated with IUGR placentas. Indeed, in a study by Biron et al., there was enhanced senescence in IUGR placentas, as evident from a higher percentage of SAHF (senescence associated heterochromatin foci) in IUGR compared to controls [1]. 8. Telomere capture and IUGR When telomeres shorten to a critical length, repair pathways are recruited. In telomere capture, short telomeres acquire a new telomeric sequence from a sister chromatid or from another chromosomal end. Increased telomere capture was found in IUGR trophoblasts compared to control samples. These results suggest a compensatory response of IUGR placentas to shortened telomeres in order to maintain telomere length and function [1]. 9. Telomere length in other obstetrical conditions Hypoxia and endothelial dysfunction have been linked to placental insufficiency and increased risk of developing IUGR and PE. Hyperglycemia due to uncontrolled diabetes might also lead to placental injury. Telomere homeostasis is known to be influenced by environmental stressors, including hypoxia and hyperglycemia, and may therefore implicate an association between telomere abnormalities and placental patopogy, induced by different stressors [2,37,38]. PE, which is a pregnancy specific pathology, is characterized by hypertension and proteinuria, and reflects placental dysfunction. Abundant trophoblasts with short telomeres were found in placentas from preeclamptic pregnancies, with and without concurrent IUGR. Whereas increased aggregate formation was found in preeclamptic placentas, this phenomenon was less pronounced in IUGR placentas, indicating these conditions affect differently on placental telomeres. Short telomeres and lower levels of telomerase
T. Biron-Shental et al. / Placenta 39 (2016) 21e23
were more pronounced in trophoblasts from pregnancies complicated by both IUGR and preeclampsia. These findings suggest an association between clinical characteristics, placental stress and telomere homeostasis [2,39]. Moreover, a greater percentage of trophoblasts with short telomeres and noticeably more aggregate formation were observed in placentas from patients with uncontrolled diabetes compared to controls. Poorly controlled diabetes is also related to increased trophoblastic senescence. These differences were not observed in cord blood samples [40]. However, blood samples from fetuses born to diabetic mothers had shorter telomeres compared to those who were born to healthy mothers, whereas no differences in telomere homeostasis were found between samples from healthy controls and fetuses born to mothers with preeclampsia or gestational hypertension [41]. Obviously, various intrauterine insults affect placental and fetal telomere homeostasis differently. It seems that some of the telomere abnormalities are restricted to the placenta. Data regarding telomere homeostasis in cord and in fetal blood samples are very limited, and supported by relatively small, observational studies [40]. Research directed toward mechanistic analysis and interventional models will be important, and may provide insight into new methods for treatment and prevention of placental diseases.
[13] [14]
[15]
[16]
[17]
[18] [19]
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[23]
[24]
10. Conclusions and future directions The information presented in this review associates telomere shortening and IUGR related placental insufficiency. Impaired telomere homeostasis might play a role in the pathophysiology of IUGR and might affect intrauterine programming related to the origin of some diseases that arise in adults [1]. Future investigations in this field should consider comparing telomere homeostasis in early versus late onset of placenta-mediated IUGR, as well as potential benefits of interventions such as oxygen supplementation. Studies with cultured human trophoblasts might enable a more mechanistic understanding of placental injury and interventions that may change the course of placenta-mediated IUGR. References [1] T. Biron-Shental, R. Sukenik-Halevy, Y. Sharon, I. Laish, M.D. Fejgin, A. Amiel, Telomere shortening in intra uterine growth restriction placentas, Early Hum. Dev. 90 (2014) 465e469. [2] T. Biron-Shental, R. Sukenik-Halevy, Y. Sharon, L. Goldberg-Bittman, D. Kidron, M.D. Fejgin, et al., Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction, Am. J. Obstet. Gynecol. 202 (2010) 381 e1e7. [3] H.J. Muller, The remaking of chromosomes, Collect. Net. 13 (1938) 181e198. [4] B. McClintock, The stability of broken ends of chromosomes, Genetics 26 (1941) 234e282. [5] M.A. Blasco, S.M. Gasser, J. Lingner, Telomeres and telomerase, Genes Dev. 13 (1999) 2353e2359. [6] C.W. Greider, Telomeres, telomerase and senescence, Bioessays 12 (1990) 363e369. [7] C.B. Harley, A.B. Futcher, C.W. Greider, Telomeres shorten during aging of human fibroblasts, Nature 345 (1990) 458e460. [8] T. von Zglinicki, G. Saretzki, W. Docke, Lotze Cl, Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp. Cell Res. 220 (1995) 186e193. [9] M. Armanios, Telomeres and age-related disease: how telomere biology informs clinical paradigms, J. Clin. Invest 123 (2013) 996e1002. [10] R.C. Allsop, C.B. Harley, Evidence of a critical telomere length in senescent human fibroblasts, Exp. Cell Res. 219 (1995) 130e136. [11] C.W. Greider, Mammalian telomere dynamics: healing, fragmentation shortening and stabilization, Curr. Opin. Genet. Dev. 4 (1994) 203e211. [12] T. Biron-Shental, R. Sukenik-Halevy, L. Goldberg-Bittman, D. Kidron, M.D. Fejgin, A. Amiel, Telomeres are shorter in placental trophoblasts of
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pregnancies complicated with intrauterine growth restriction (IUGR), Early Hum. Dev. 86 (2010) 451e456. P.J. Mason, N. Perdigones, Telomere biology and translational research, Transl. Res. 162 (6) (2013) 333e342. ~ nez, E. Heard, M. Narita, A.W. Lin, S.A. Hearn, et al., RbM. Narita, S. Nu mediated heterochromatin formation and silencing of E2F target genes during cellular senescence, Cell 113 (2003) 703e716. J.L. Sanders, A.B. Newman, Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? Epidemiol. Rev. 35 (2013) 112e131. I.M. Wentzensen, L. Mirabello, R.M. Pfeiffer, S.A. Savage, The association of telomere length and cancer: a meta-analysis, Cancer Epidemiol. Biomarkers Prev. 20 (2011) 1238e1250. H. Ma, Z. Zhou, S. Wei, Z. Liu, K.A. Pooley, A.M. Dunning, et al., Shortened telomere length is associated with increased risk of cancer: a meta-analysis, PLoS One 6 (2011) e20466. J. Zhao, K. Miao, H. Wang, H. Ding, D.W. Wang, Association between telomere length and diabetes mellitus: a meta-analysis, PLoS One 8 (2013) e79993. P.C. Haycock, E.E. Heydon, S. Kaptoge, A.S. Butterworth, A. Thompson, P. Willeit, Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis, BMJ 349 (2014) g4227. American College of Obstetricians and Gynecologists, ACOG practice bulletin no. 134: Fetal growth restriction, Obstet. Gynecol. 121 (2013) 1122e1133. J.W. Seeds, T. Peng, Impaired growth and risk of fetal death: is the tenth percentile the appropriate standard? Am. J. Obstet. Gynecol. 178 (1998) 658e659. C.M. Salafia, V.K. Minior, J.C. Pezzullo, E.J. Popek, T.S. Rosenkrantz, A.M. Vintzileos, Intrauterine growth restriction in infants of less than thirtytwo weeks gestation: associated placental pathologic features, Am. J. Obstet. Gynecol. 173 (1995) 1049e1057. E.K. Pallotto, H.W. Kilbride, Perinatal outcome and later implications of intrauterine growth restriction, Clin. Obstet. Gynecol. 49 (2006) 257e269. D.J. Barker, Adult consequences of fetal growth restriction, Clin. Obstet. Gynecol. 49 (2006) 270e283. R. Aviram, T. Biron-Shental, D. Kidron, Placental aetiologies of foetal growth restriction: clinical and pathological differences, Early Hum. Dev. 86 (2010) 59e63. S. Entringer, C. Buss, P.D. Wadhwa, Prenatal stress, telomere biology, and fetal programming of health and disease risk, Sci. Signal 5 (pt. 12) (2012). D.D. Mcintire, S.S. Bloom, B.M. Casey, K.J. Leveno, Birth weight in relation to morbidity and mortality among infants, N. Engl. J. Med. 340 (1999) 1234e1238. D.J. Barker, C. Osmond, J. Golding, D. Kuh, M.E. Wadsworth, Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease, BMJ 298 (1989) 564e567. D.J. Barker, A.R. Bull, C. Osmond, S.J. Simmonds, Fetal and placental size and risk of hypertension in adult life, BMJ 301 (1990) 259e262. D.J. Barker, Fetal origins of coronary heart disease, BMJ 311 (1995) 171e174. C.N. Hales, D.J. Barker, The thrifty phenotype hypothesis, Br. Med. Bull. 60 (2001) 5e20. T. Izutsu, T. Kudo, T. Sato, I. Nishiya, K. Ohyashiki, M. Mori, et al., Telomerase activity in human chorionic villi and placenta determined by TRAP and in situ TRAP assay, Placenta 19 (1998) 613e618. J. Toutain, M. Prochazkova-Carlotti, D. Cappellen, A. Jarne, E. Chevret, J. Ferre, et al., Reduced placental telomere length during pregnancies complicated by intrauterine growth restriction, PLoS One 8 (1) (2013) e54013. P. Davy, M. Nagata, P. Bullard, N.S. Fogelson, R. Allsopp, Fetal growth restriction is associated with accelerated telomere shortening and increased expression of cell senescence markers in the placenta, Placenta 30 (2009) 539e542. T. Biron-Shental, D. Kidron, R. Sukenik-Halevy, L. Goldberg-Bittman, R. Sharony, M.D. Fejgin, et al., TERC telomerase subunit gene copy number in placentas from pregnancies complicated with intrauterine growth restriction, Early Hum. Dev. 87 (2011) 73e75. V. Cattan, N. Mercier, J.P. Gardner, et al., Chronic oxidative stress induces a tissue-specific reduction in telomere length in CAST/Ei mice, Free Radic. Biol. Med. 44 (2008) 1592e1598. H. Nishi, T. Nakada, S. Kyo, M. Inoue, J.W. Shay, K. Isaka, Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT), Mol. Cell Biol. 24 (2004) 6076e6083. R. Sukenik-Halevy, M. Fejgin, D. Kidron, L. Goldberg-Bittman, R. Sharony, T. Biron-Shental, Y. Kitay-Cohen, A. Amiel, Telomere aggregate formation in placenta specimens of pregnancies complicated with pre-eclampsia, Cancer Genet. Cytogenet 195 (1) (2009) 27e30. T. Biron-Shental, R. Sukenik-Halevy, H. Naboani, M. Liberman, R. Kats, A. Amiel, Telomeres are shorter in placentas from pregnancies with uncontrolled diabetes, Placenta 36 (2) (2015) 199e203. J. Xu, J. Ye, Y. Wu, H. Zhang, Q. Luo, et al., Reduced Fetal Telomere Length in Gestational Diabetes, PLoS ONE 9 (1) (2014) e86161.
Contents lists available at ScienceDirect
Placenta journal homepage: www.elsevier.com/locate/placenta
Telomere homeostasis in IUGR placentas e A review Tal Biron-Shental a, b, *, Dana Sadeh-Mestechkin a, b, Aliza Amiel a, b a b
Department of Maternal-Fetal Medicine, Meir Medical Center, Kfar Saba, Israel Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
a r t i c l e i n f o
a b s t r a c t
Article history: Received 29 May 2015 Received in revised form 13 November 2015 Accepted 18 November 2015
Telomeres are nucleoprotein structures located at the termini of chromosomes. They are essential for chromosome stability. Telomeres become shorter due to mitotic cycles and environmental factors. When telomeres are shortened and therefore dysfunctional, cellular senescence occurs and organ dysfunction might develop. During pregnancy, fetal growth restriction secondary to placental insufficiency has been linked to impaired telomere homeostasis in which telomeres are shorter, telomerase is decreased, and compensatory mechanisms of telomere capture are enhanced. These characteristics, along with increased signs of senescence, indicate telomere dysfunction in trophoblasts from placentas affected by intrauterine growth restriction (IUGR). This review summarizes the information currently available regarding telomere homeostasis in trophoblasts from human pregnancies affected by IUGR. Improved understanding of placental physiology might help in the development of treatment options for fetuses with IUGR. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Placenta Trophoblasts IUGR Telomeres
1. Telomeres Telomeres are nucleoprotein structures consisting of 5e15 kilobase pairs of repetitive DNA sequences, located at the termini of chromosomes [1]. They are essential for chromosome stability and cell survival, and protect the chromosomes from end-to-end fusion and degradation [2e5]. Telomeres become progressively shorter with each mitotic cycle. They are also shortened by environmental factors, such as oxidative stress [1,2,5e9]. Short telomeres promote cell cycle arrest, apoptosis, and genomic instability [2,6,7]. Once telomeres reach a critically short length, cell senescence is triggered, leading to a process of tissue aging [2,6,7,10]. Dysfunctional telomeres also tend to fuse end-to-end, forming aggregates, irrespective of their length [2]. Telomere length is regulated by telomere-associated proteins; primarily the telomerase enzyme, which adds telomeric repeats to the ends of chromosomes [2,6,11]. Human telomerase reverse transcriptase (hTERT) is the catalytic component of telomerase, and is considered the rate-limiting factor in telomerase activity. A lack of telomerase in normal human cells leads to a progressive decrease in telomere length, resulting in cell senescence and tissue dysfunction [2,6,10,11].
* Corresponding author. Department of Obstetrics and Gynecology, Meir Medical Center, 59 Tschernihovsky, Kfar Saba 44282, Israel. E-mail address: [email protected] (T. Biron-Shental). http://dx.doi.org/10.1016/j.placenta.2015.11.006 0143-4004/© 2016 Elsevier Ltd. All rights reserved.
One component of telomerase, which serves as the RNA template for the addition of telomeric repeats, is encoded by the telomerase RNA component gene (TERC). TERC encodes telomerase and is located at the human chromosome band 3q26. Amplification of this gene is correlated with increased telomeric repeats that prevent telomere shortening and cellular senescence [12]. Senescence is an arrest of cellular proliferation and is involved in the biological process of tissue aging. It is driven by cell division, as well as by oxidative stress, DNA damage and repair response, inflammation, and telomere shortening. Nuclei in senescent human cells are often granulated, containing senescence-associated heterochromatin foci (SAHF) [1,13,14]. When telomeres become critically short, repair pathways are recruited. One such pathway is telomere capture, through which a short telomere acquires a new telomere sequence from a sister chromatid or from another chromosomal end [1]. Telomere length has been studied primarily as a general risk factor for age-related, chronic diseases such as type II diabetes, cardiovascular diseases and malignancies [15e18]. The length of telomeres in leukocytes is inversely related to the risk of developing cancer, diabetes and cardiovascular disease [19]. Shortened and therefore dysfunctional telomeres may cause organ damage and early aging, which consequently lead to diseases. These data also suggest that telomere homeostasis may play a role in human trophoblasts [15e19], as one of the mechanisms underlying placental pathologies.
22
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2. Intrauterine growth restriction (IUGR) The most common definition of IUGR refers to fetuses with an estimated weight below the 10th percentile for gestational age [21,22]. IUGR can be related to a combination of maternal, fetal, and placenta factors. The most common etiology is abnormal placentation, which results in poor placental perfusion (i.e., placental insufficiency) with subsequent effects on the fetus [21,23]. IUGR increases the risk of intrauterine fetal death, and neonatal morbidity and mortality. Intrauterine insults can cause permanent structural and functional changes to the fetus, which may disrupt postnatal development and increase morbidity and mortality [27,28]. Long-term effects of placental insult persist into adulthood, and include type 2 diabetes mellitus, coronary artery disease, stroke and the metabolic syndrome [24,25,29e32]. Morphometric and microscopic differences are evident between normal placentas and those associated with IUGR. Gross findings in IUGR placentas include low placental weight, thin umbilical cord and parenchymal loss (infarcts). Histological changes also reflect chronic placental ischemia due to maternal or fetal blood supply abnormalities and protein synthesis inhibition, secondary to endoplasmic reticulum stress [26]. This review focuses on telomere homeostasis in placentas from pregnancies complicated with IUGR due to placental insufficiency.
gene copy. TERC serves as the RNA template for the addition of telomeric repeats [36]. Comparison of the number of copies of the TERC gene between IUGR and control placentas at the same gestational age revealed fewer copies of TERC in IUGR placentas, yet these results were not replicated by other research [34]. Toutain et al. used cultured villi obtained from late chorionic villus samples. Patients with severe IUGR (below the third percentile) and controls undergoing prenatal diagnosis for other indications underwent invasive prenatal diagnosis. Quantitative-PCR revealed shorter mean telomere length in the IUGR pregnancies, but no difference in the number of TERC copies. These results may be explained by the timing of placental sampling (early during pregnancy versus the placenta at birth), as well as the small number of samples studied [36]. 6. Telomere aggregates and IUGR An increased number of aggregates were found in preeclampsia (PE), which is also associated with placental insufficiency and short telomeres [2]. Trophoblasts from IUGR placentas tended to have more aggregates compared to controls [12], but the difference was not statistically significant. Another study found no difference in the percentage of aggregates between IUGR and control placentas [2]. The different results from women with or IUGR may reflect variations in the pathophysiology of these two conditions [2].
3. Telomere length and IUGR 7. Senescence and IUGR IUGR can be caused by placental insufficiency, which in some cases may be related to oxidative stress and to intrauterine hypoxia. As noted, telomere length is also influenced by these factors. It has been previously shown that oxidative stress leads to telomere shortening in cultured cells. These observations raised the question of telomere length in IUGR placentas [12]. Several studies have shown that telomeres in placental trophoblasts of pregnancies complicated with IUGR are shorter than uncomplicated pregnancies [1,2,12,33e36]. Davy et al. analyzed telomers length in IUGR (defined as birth weight below 5%) and control placentas. Using Southern blot analysis they found a shorter telomere length in IUGR placentas. Similar results were shown by Biron et al. (IUGR defined as birth weight below 10%), using quantitative FISH [2,12]. These telomere lengths were measured on placentas collected at deliveries from pregnancies complicated by IUGR secondary to placental insufficiency. The results are consistent with observations from a study performed by Toutain at al. They analyzed telomere length on villi obtained from late (chorionic villous sampling) CVS in pregnancies with severe IUGR [34]. Interestingly, no difference in telomere length was found in cord blood leukocytes taken from IUGR and control pregnancies [35], suggesting that the cause may be different, or that different mechanisms, regulate telomere length in fetal blood and in the placenta [12]. 4. Human telomerase reverse transcriptase (hTERT) and IUGR Telomerase activity is suppressed in IUGR placentas compared to placentas from healthy controls at the same gestational age [31]. The level of human telomerase reverse transcriptase (hTERT), the catalytic unit of telomerase, corresponds to telomere elongation. Decreased hTERT expression in IUGR placentas suggests that lower telomerase activity short telomeres in these placentas [12]. 5. Telomerase RNA component gene (TERC) and IUGR The mechanism of telomere shortening in placental dysfunction is not well understood. One possible explanation is decreased TERC
The relationship between cellular senescence and telomere shortening is well-established [1,7,13,14]. Since factors such as oxidative stress and hypoxia, which are known as senescence accelerators, may cause placental damage and IUGR, senescence may be associated with IUGR placentas. Indeed, in a study by Biron et al., there was enhanced senescence in IUGR placentas, as evident from a higher percentage of SAHF (senescence associated heterochromatin foci) in IUGR compared to controls [1]. 8. Telomere capture and IUGR When telomeres shorten to a critical length, repair pathways are recruited. In telomere capture, short telomeres acquire a new telomeric sequence from a sister chromatid or from another chromosomal end. Increased telomere capture was found in IUGR trophoblasts compared to control samples. These results suggest a compensatory response of IUGR placentas to shortened telomeres in order to maintain telomere length and function [1]. 9. Telomere length in other obstetrical conditions Hypoxia and endothelial dysfunction have been linked to placental insufficiency and increased risk of developing IUGR and PE. Hyperglycemia due to uncontrolled diabetes might also lead to placental injury. Telomere homeostasis is known to be influenced by environmental stressors, including hypoxia and hyperglycemia, and may therefore implicate an association between telomere abnormalities and placental patopogy, induced by different stressors [2,37,38]. PE, which is a pregnancy specific pathology, is characterized by hypertension and proteinuria, and reflects placental dysfunction. Abundant trophoblasts with short telomeres were found in placentas from preeclamptic pregnancies, with and without concurrent IUGR. Whereas increased aggregate formation was found in preeclamptic placentas, this phenomenon was less pronounced in IUGR placentas, indicating these conditions affect differently on placental telomeres. Short telomeres and lower levels of telomerase
T. Biron-Shental et al. / Placenta 39 (2016) 21e23
were more pronounced in trophoblasts from pregnancies complicated by both IUGR and preeclampsia. These findings suggest an association between clinical characteristics, placental stress and telomere homeostasis [2,39]. Moreover, a greater percentage of trophoblasts with short telomeres and noticeably more aggregate formation were observed in placentas from patients with uncontrolled diabetes compared to controls. Poorly controlled diabetes is also related to increased trophoblastic senescence. These differences were not observed in cord blood samples [40]. However, blood samples from fetuses born to diabetic mothers had shorter telomeres compared to those who were born to healthy mothers, whereas no differences in telomere homeostasis were found between samples from healthy controls and fetuses born to mothers with preeclampsia or gestational hypertension [41]. Obviously, various intrauterine insults affect placental and fetal telomere homeostasis differently. It seems that some of the telomere abnormalities are restricted to the placenta. Data regarding telomere homeostasis in cord and in fetal blood samples are very limited, and supported by relatively small, observational studies [40]. Research directed toward mechanistic analysis and interventional models will be important, and may provide insight into new methods for treatment and prevention of placental diseases.
[13] [14]
[15]
[16]
[17]
[18] [19]
[21] [22]
[23]
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10. Conclusions and future directions The information presented in this review associates telomere shortening and IUGR related placental insufficiency. Impaired telomere homeostasis might play a role in the pathophysiology of IUGR and might affect intrauterine programming related to the origin of some diseases that arise in adults [1]. Future investigations in this field should consider comparing telomere homeostasis in early versus late onset of placenta-mediated IUGR, as well as potential benefits of interventions such as oxygen supplementation. Studies with cultured human trophoblasts might enable a more mechanistic understanding of placental injury and interventions that may change the course of placenta-mediated IUGR. References [1] T. Biron-Shental, R. Sukenik-Halevy, Y. Sharon, I. Laish, M.D. Fejgin, A. Amiel, Telomere shortening in intra uterine growth restriction placentas, Early Hum. Dev. 90 (2014) 465e469. [2] T. Biron-Shental, R. Sukenik-Halevy, Y. Sharon, L. Goldberg-Bittman, D. Kidron, M.D. Fejgin, et al., Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction, Am. J. Obstet. Gynecol. 202 (2010) 381 e1e7. [3] H.J. Muller, The remaking of chromosomes, Collect. Net. 13 (1938) 181e198. [4] B. McClintock, The stability of broken ends of chromosomes, Genetics 26 (1941) 234e282. [5] M.A. Blasco, S.M. Gasser, J. Lingner, Telomeres and telomerase, Genes Dev. 13 (1999) 2353e2359. [6] C.W. Greider, Telomeres, telomerase and senescence, Bioessays 12 (1990) 363e369. [7] C.B. Harley, A.B. Futcher, C.W. Greider, Telomeres shorten during aging of human fibroblasts, Nature 345 (1990) 458e460. [8] T. von Zglinicki, G. Saretzki, W. Docke, Lotze Cl, Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp. Cell Res. 220 (1995) 186e193. [9] M. Armanios, Telomeres and age-related disease: how telomere biology informs clinical paradigms, J. Clin. Invest 123 (2013) 996e1002. [10] R.C. Allsop, C.B. Harley, Evidence of a critical telomere length in senescent human fibroblasts, Exp. Cell Res. 219 (1995) 130e136. [11] C.W. Greider, Mammalian telomere dynamics: healing, fragmentation shortening and stabilization, Curr. Opin. Genet. Dev. 4 (1994) 203e211. [12] T. Biron-Shental, R. Sukenik-Halevy, L. Goldberg-Bittman, D. Kidron, M.D. Fejgin, A. Amiel, Telomeres are shorter in placental trophoblasts of
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