Oxidative Stress and the Induction of Cyclooxygenase Enzymes and Apoptosis in the Murine Placenta
Open accessAbstract
Placental oxidative stress has been implicated in many complications of human pregnancy, including preterm delivery and preeclampsia. It is now appreciated that reactive oxygen species can induce a spectrum of changes, ranging from homeostatic induction of enzymes to apoptotic cell death. Little is known regarding the occurrence of placental oxidative stress in other species. We investigated markers of oxidative stress in the labyrinthine (LZ) and junctional (JZ) zones of the murine placenta across gestational age, and correlated these with expression of the cyclooxygenase enzymes COX-1 and COX-2, and apoptosis. We tested a causal link between the two by subjecting placental explants to hypoxia-reoxygenation (H/R) in vitro, a known stimulus for generation of oxidative stress. Western blotting demonstrated significant increases in the concentrations of hydroxynonenal (HNE), COX-1 and COX-2 with gestational age. Dual-labelling demonstrated co-localisation of HNE, and COX-1 and COX-2 within the trophoblast of the LZ, and glycogen cells of the JZ. An apoptotic index based on TUNEL-positivity demonstrated an increase with gestational age, and dual-labelling showed co-localisation of TUNEL labelling with HNE and active caspase-3 within the trophoblast of the LZ. H/R significantly increased oxidative stress, induction of COX-1 and COX-2, and the apoptotic index. Co-localisation demonstrated the increases in COX to be within the trophoblast of the LZ, and in particular the glycogen cells of the JZ. Apoptosis was restricted to the LZ. We speculate that the induction of COX enzymes is a physiological response to oxidative stress, and may play a role in initiating or augmenting parturition. Generation of oxidative stress may also play a role in influencing the growth trajectory of the placenta, and its component cell types. The mouse may provide an experimental genetic model in which to investigate these phenomena.
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The prolonged gestation interval observed in the ERKdko females was reminiscent of phenotype described for the cyclooxygenase 1 (PGHS1/COX1) knockout animal.
“First, the prolonged gestation interval observed in the ERKdko females was reminiscent of phenotype described for the cyclooxygenase 1 (PGHS1/COX1) knockout animal34–39.”
From Conditional loss of ERK1 and ERK2 results in abnormal placentation and delayed parturition in the mouse (2019) · cites this paper as [38]
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Latest Advances in Understanding Preeclampsia
Redman, C. W., & Sargent, I. L. (2005) · Science · doi:10.1126/science.1111726 · Cited by 2,607 · cited 2× · see citing works
“It is thought that microparticles of apoptotic, or aponecrotic, debris released from the apical surface of the syncytiotrophoblast into the maternal circulation result in an enhanced maternal inflammatory response in preeclampsia [6].”
BackgroundOxidative stress in the placenta
Myatt, L., & Cui, X.-L. (2004) · Histochemistry and Cell Biology · doi:10.1007/s00418-004-0677-x · Cited by 803 · cited 1× · see citing works
“Oxidative stress of the placenta has been implicated in the pathogenesis of many complications of human pregnancy, including miscarriage, preeclampsia, and preterm labour [1–3].”
BackgroundPlacental oxidative stress: from miscarriage to preeclampsia
Burton, G. J., & Jauniaux, E. (2004) · Journal of the Society for Gynecologic Investigation · doi:10.1016/j.jsgi.2004.03.003 · Cited by 673 · cited 1× · see citing works
“We have recently proposed that placental oxidative stress arises through fluctuations in oxygenation [3,25], and its development in the murine placenta towards term is consistent with this view.”
ResultSelf-citationOxidative Stress in the Pathogenesis of Preeclampsia
Hubel, C. A. (1999) · Proceedings of The Society for Experimental Biology and Medicine · doi:10.1046/j.1525-1373.1999.d01-139.x · Cited by 673 · see citing works
Comparative Developmental Anatomy of the Murine and Human Definitive Placentae
Georgiades, P., Ferguson-Smith, A. C., & Burton, G. J. (2002) · Placenta · doi:10.1053/plac.2001.0738 · Cited by 641 · see citing works
Self-citationJauniaux, E. R. M., Poston, L., & Burton, G. J. (2006) · Human Reproduction Update · doi:10.1093/humupd/dml016 · Cited by 608 · cited 1× · see citing works
“We have recently proposed that placental oxidative stress arises through fluctuations in oxygenation [3,25], and its development in the murine placenta towards term is consistent with this view.”
ResultSelf-citationThe myometrial junctional zone spiral arteries in normal and abnormal pregnancies
Brosens, J. J., Pijnenborg, R., & Brosens, I. A. (2002) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2002.127305 · Cited by 536 · see citing works
Ishihara, N., Matsuo, H., Murakoshi, H., Laoag‐Fernandez, J. B., Samoto, T., & Maruo, T. (2002) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2002.119176 · Cited by 509 · see citing works
Placental apoptosis in preeclampsia
Allaire, A. D. (2000) · Obstetrics and Gynecology · doi:10.1016/s0029-7844(00)00895-4 · Cited by 416 · see citing works
Placental apoptosis in normal human pregnancy
SMITH, S. C. H., Baker, P. N., & SYMONDS, E. M. (1997) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(97)70438-1 · Cited by 400 · cited 1× · see citing works
“Apoptosis increases towards term in normal human pregnancies [36], but increased rates have been reported in preeclamptic placentas and in placentas from cases of intrauterine growth restriction [37e39].”
BackgroundHung, T., Skepper, J. N., Jones, D. S., & Burton, G. J. (2002) · Circulation Research · doi:10.1161/01.res.0000024411.22110.aa · Cited by 397 · cited 2× · see citing works
“As in the human placenta this was associated with increased concentrations of active caspase-3 [20].”
BackgroundSelf-citationEvidence for Involvement of NF-κB in the Transcriptional Control of COX-2 Gene Expression by IL-1β
Newton, R. C., Kuitert, L. M. E., Bergmann, M., Adcock, I. M., & Barnes, P. J. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7064 · Cited by 390 · see citing works
Increased placental apoptosis in intrauterine growth restriction
SMITH, S. C. H., Baker, P. N., & SYMONDS, E. M. (1997) · American Journal of Obstetrics and Gynecology · doi:10.1016/s0002-9378(97)70081-4 · Cited by 374 · see citing works
Allport, V. C. (2001) · Molecular Human Reproduction · doi:10.1093/molehr/7.6.581 · Cited by 308 · see citing works
Developmental Dynamics of the Definitive Mouse Placenta Assessed by Stereology1
Coan, P. M., Ferguson-Smith, A. C., & Burton, G. J. (2004) · Biology of Reproduction · doi:10.1095/biolreprod.103.024166 · Cited by 296 · cited 1× · see citing works
“5 [35].”
Self-citationHung, T., Skepper, J. N., & Burton, G. J. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)61778-6 · Cited by 289 · cited 2× · see citing works
“In order to induce oxidative stress placental samples were subjected to hypoxia-reoxygenation (H/R) in vitro [22].”
MethodSelf-citationKim, Y. M., Chaiworapongsa, T., Gómez, R., Bujold, E., Yoon, B. H., Rotmensch, S., Thaler, H. T., & Romero, R. J. (2002) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2002.127720 · Cited by 280 · see citing works
The contribution of placental oxidative stress to early pregnancy failure
Hempstock, J., Jauniaux, E. R. M., Greenwold, N., & Burton, G. J. (2003) · Human Pathology · doi:10.1016/j.humpath.2003.08.006 · Cited by 260 · cited 1× · see citing works
“dard protocol [21].”
Self-citationOrigin and characteristics of glycogen cells in the developing murine placenta
Coan, P. M., Conroy, N., Burton, G. J., & Ferguson‐Smith, A. C. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20981 · Cited by 243 · see citing works
Self-citationOpposing actions of prostaglandins and oxytocin determine the onset of murine labor
Gross, G. A., Imamura, T., Luedke, C., Vogt, S. K., Olson, L. M., Nelson, D. M., Sadovsky, Y., & Muglia, L. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.20.11875 · Cited by 238 · cited 2× · see citing works
“For example, prostaglandins (PGs) are central components of labour in both humans and mice [11].”
BackgroundGuan, Z., Buckman, S. Y., Miller, B. W., Springer, L. D., & Morrison, A. R. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.44.28670 · Cited by 233 · see citing works
Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse.
Gross, G., Imamura, T., Vogt, S. K., Wozniak, D. F., Nelson, D., Sadovsky, Y., & Muglia, L. J. (2000) · American Journal of Physiology. Regulatory Integrative and Comparative Physiology · doi:10.1152/ajpregu.2000.278.6.r1415 · Cited by 150 · cited 1× · see citing works
“In mice induction of COX-2 by administration of lipopolysaccharide leads to preterm labour, which can be blocked using the specific COX-2 inhibitor SC-236 [18].”
BackgroundReese, J., Paria, B. C., Brown, N., Zhao, X., Morrow, J. D., & Dey, S. K. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.17.9759 · Cited by 146 · cited 1× · see citing works
“As PGs have been linked with the induction of parturition [10,11,33] this raises the possibility that placental oxidative stress could play a role in initiating or augmenting uterine contractions should the mismatch in maternal blood supply and feto-placental demands become extreme.”
BackgroundAllport, V. C. (2000) · Molecular Human Reproduction · doi:10.1093/molehr/6.6.561 · Cited by 143 · see citing works
ARIAS, F., Victoria, A., Cho, K. H., & Kraus, F. T. (1997) · Obstetrics and Gynecology · doi:10.1016/s0029-7844(96)00451-6 · Cited by 130 · cited 1× · see citing works
“Placental inflammatory lesions have also been associated with premature onset of labour [7].”
BackgroundOxidative stress in the pathogenesis of preeclampsia.
Hubel, C. A. (1999) · PubMed · doi:10.1177/153537029922200305 · Cited by 106 · cited 1× · see citing works
“Oxidative stress of the placenta has been implicated in the pathogenesis of many complications of human pregnancy, including miscarriage, preeclampsia, and preterm labour [1–3].”
BackgroundCoan, P. M., Ferguson‐Smith, A. C., & Burton, G. J. (2005) · Journal of Anatomy · doi:10.1111/j.1469-7580.2005.00488.x · Cited by 94 · cited 1× · see citing works
“The trophoblast comprises three layers; an outer layer (I) composed of cytotrophoblast cells, and two layers (II & III) of syncytiotrophoblast [9].”
BackgroundSelf-citationKadyrov, M., Kaufmann, P., & Huppertz, B. (2001) · Placenta · doi:10.1053/plac.2000.0616 · Cited by 92 · see citing works
Bártková, J., Meyts, E. R., Skakkeb�k, N. E., & Bártek, J. (1999) · The Journal of Pathology · doi:10.1002/(sici)1096-9896(199904)187:5 · Cited by 74 · see citing works
Malek, A., Sager, R., & Schneider, H. (2001) · Placenta · doi:10.1053/plac.2001.0635 · Cited by 62 · cited 1× · see citing works
“Evidence from other systems points to potential links between oxidative stress and COX induction, resulting in the production of PGs [12–16].”
BackgroundKniss, D. A., Rovin, B. H., Fertel, R. H., & Zimmerman, P. D. (2001) · Placenta · doi:10.1053/plac.2000.0591 · Cited by 57 · see citing works
Mouse Placental Prostaglandins Are Associated with Uterine Activation and the Timing of Birth1
Cook, J. L., Shallow, M. C., Zaragoza, D. B., Anderson, K. I., & Olson, D. M. (2003) · Biology of Reproduction · doi:10.1095/biolreprod.102.008789 · Cited by 46 · cited 2× · see citing works
“The mechanisms of myometrial stimulation and activation appear to parallel those of the human [10].”
BackgroundGene Knockout Mice in the Study of Parturitions
Gross, G., Imamura, T., & Muglia, L. J. (2000) · Journal of the Society for Gynecologic Investigation · doi:10.1177/107155760000700202 · Cited by 40 · cited 1× · see citing works
“However, these contrasting roles have not been proven in the mouse [17].”
BackgroundSugino, N., Karube-Harada, A., Kashida, S., Takiguchi, S., & Kato, H. (2001) · Human Reproduction · doi:10.1093/humrep/16.9.1797 · Cited by 35 · see citing works
White, V., Jawerbaum, A., Sinner, D. I., Pustovrh, M. C., Capobianco, E., & González, E. (2002) · Reproduction Fertility and Development · doi:10.1071/rd01032 · Cited by 28 · see citing works
Gene knockout mice in the study of parturition
Gross, G. (2000) · Journal of the Society for Gynecologic Investigation · doi:10.1016/s1071-5576(99)00075-1 · Cited by 27 · see citing works
Expression of Apoptosis in Placentae from Mice Lacking the Prostaglandin F Receptor
Mu, J., Kanzaki, T., Tomimatsu, T., Fukuda, H., Wasada, K., Fujii, E., Endoh, M., Kozuki, M., Murata, Y., Sugimoto, Y., et al. (2002) · Placenta · doi:10.1053/plac.2001.0759 · Cited by 26 · cited 1× · see citing works
“Apoptosis has been described within the LZ of the normal mouse placenta, and is most frequent towards term and in post-mature placentas [19].”
BackgroundXu, Y., Knipp, G. T., & Cook, T. J. (2005) · Molecular Pharmaceutics · doi:10.1021/mp0500519 · Cited by 25 · cited 1× · see citing works
“Expression of COX-1 and COX-2 has recently been reported in the rat placenta, and that of COX-2 similarly increases with gestational age, particularly in the JZ [32].”
BackgroundExpression of Apoptosis in Placentas from Mice Lacking the Prostaglandin F Receptor
穆, 俊. (2002) · Cited by 19 · see citing works
Iqbal, M., Giri, U., Giri, D. K., & Athar, M. S. (1997) · IUBMB Life · doi:10.1080/15216549700203581 · Cited by 17 · see citing works
Effect of hydrogen peroxide on prostaglandin production and contractions of the pregnant rat uterus
Cherouny, P. H., Ghodgaonkar, R. B., Niebyl, J. R., & Dubin, N. H. (1988) · American Journal of Obstetrics and Gynecology · doi:10.1016/0002-9378(88)90562-5 · Cited by 17 · see citing works
Blood gas tensions and acid-base status in the fetal guinea-pig.
Carter, A. M., & Grønlund, J. (1982) · PubMed · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kell, D. B. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-2 · Cited by 554 · see citing works
“this [425-489], while some have noted the importance of”
BackgroundAgarwal, A. K., Gupta, S., Sekhon, L. H., & Shah, R. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1964 · Cited by 360 · see citing works
“A possible mechanism is that OS levels increase with increasing gestational age, leading to elevated concentration of COX-1 and COX-2 enzymes, possibly through activation of p38 MAPK and nuclear factor kappa beta pathways (36).”
Oxidative Stress, Gene Expression, and Protein Changes Induced in the Human Placenta during Labor
Cindrová‐Davies, T., Yung, H. W., Johns, J., Spasić-Bošković, O., Korolchuk, S., Jauniaux, E. R. M., Burton, G. J., & Jones, D. S. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.070528 · Cited by 296 · see citing works
“between oxidative stress and increased concentrations of COX enzymes has recently been reported in the murine placenta.(33) Table 2.”
BackgroundSelf-citationThe Placenta and Intrauterine Programming
Fowden, A. L., Forhead, A. J., Coan, P. M., & Burton, G. J. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2008.01663.x · Cited by 267 · see citing works
Self-citationIntrauterine trophoblast migration: A comparative view of humans and rodents
Silva, J. F., & Serákides, R. (2016) · Cell Adhesion & Migration · doi:10.1080/19336918.2015.1120397 · Cited by 177 · see citing works
“The spongiotrophoblasts are ovoid and mononuclear, while the glycogen cells, which appear in the placenta from the 12 day of gestation, possess more condensed nuclei and have glycogen granules in their cytoplasm.(68,71) CELL ADHESION & MIGRATION 91”
BackgroundMitochondrial – Endoplasmic reticulum interactions in the trophoblast: Stress and senescence
Burton, G. J., Yung, H. W., & Murray, A. J. (2016) · Placenta · doi:10.1016/j.placenta.2016.04.001 · Cited by 155 · see citing works
“An increase in oxidative stress is observed during late gestation in the labyrinth zone that performs gaseous exchange in the mouse [103], and is associated with an increase in the mitochondrial DNA copy number [104].”
BackgroundSelf-citationCureton, N., Korotkova, I., Baker, B., Greenwood, S. L., Wareing, M., Kotamraju, V. R., Teesalu, T., Cellesi, F., Tirelli, N., Ruoslahti, E. I., et al. (2017) · Theranostics · doi:10.7150/thno.19678 · Cited by 102 · see citing works
“Oxidative stress in the mouse placenta leads to the induction of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), leading to prostaglandin synthesis and elevated rates of apoptosis [37].”
BackgroundVornic, I., Buciu, V. B., Furau, C. G., Gaje, P. N., Ceauşu, R. A., Dumitru, C. Ș., Barb, A. C., Novacescu, D., Cumpănaş, A. A., Latcu, S. C., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212195 · Cited by 114 · see citing works
“Endothelial progenitor cell dysfunction Reduced number and function of EPCs Observed in women with history of PE [150].”
Wong, M. S. K., Delansorne, R., Man, R. Y. K., Svenningsen, P., & Vanhoutte, P. M. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00288.2010 · Cited by 95 · see citing works
Human milk enhances antioxidant defenses against hydroxyl radical aggression in preterm infants
Ledo, A., Arduini, A., Asensi, M. A., Sastre, J., Escrig, R., Brugada, M., Aguar, M., Sáenz, P., & Vento, M. (2008) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.26845 · Cited by 90 · see citing works
Li, C., Raikwar, N. S., Santillan, M. K. O., Santillan, D. A., & Thomas, C. P. (2015) · Placenta · doi:10.1016/j.placenta.2015.01.004 · Cited by 81 · see citing works
“Our study also showed that, hypoxia did not change COX1 and COX2 mRNA expression although some have reported that the hypoxia mimic, CoCl2 increases COX2 but not COX1 in trophoblasts and others have reported that hypoxia reoxygenation increases COX1 and COX2 expression in murine placental explants [44,45].”
BackgroundSultana, Z., Qiao, Y., Maiti, K., & Smith, R. (2023) · Reproduction · doi:10.1530/rep-22-0278 · Cited by 68 · see citing works
Immunological Tolerance, Pregnancy, and Preeclampsia: The Roles of Semen Microbes and the Father†
Kenny, L. C., & Kell, D. B. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2017.00239 · Cited by 69 · see citing works
Yang, C., Lim, W., Park, J., Park, S., You, S., & Song, G. (2019) · Molecular Human Reproduction · doi:10.1093/molehr/gaz054 · Cited by 66 · see citing works
Silva, J. F., Vidigal, P. V. T., Galvão, D. D., Boeloni, J. N., Nunes, P. P., Ocarino, N. M., Nascimento, E. F., & Serákides, R. (2012) · Reproduction Fertility and Development · doi:10.1071/rd11219 · Cited by 62 · see citing works
“The highest rate of apoptosis in the spongiotrophoblast layer in hypothyroid rats can also markedly affect the function of this layer because the increased apoptosis is associated with pregnancy disorders in humans (Kokawa et al. 1998; Huppertz et al. 2006; Burdon et al. 2007).”
BackgroundZhou, W., Dong, L., Du, M., Zhu, X., & Li, D. (2008) · Reproduction · doi:10.1530/rep-07-0063 · Cited by 55 · see citing works
“2002, Greer 2003, Burdon et al .”
Sun, Y., Chen, J., & Rigas, B. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn242 · Cited by 52 · see citing works
Placental inflammation and oxidative stress in the mouse model of assisted reproduction
Raunig, J. M., Yamauchi, Y., Ward, M. A., & Collier, A. C. (2011) · Placenta · doi:10.1016/j.placenta.2011.08.003 · Cited by 51 · see citing works
Kasture, V., Sundrani, D. P., & Joshi, S. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.05.029 · Cited by 46 · see citing works
Endoplasmic reticulum stress is induced in the human placenta during labour
Veerbeek, J. H. W., van Patot, M. C. T., Burton, G. J., & Yung, H. W. (2014) · Placenta · doi:10.1016/j.placenta.2014.11.005 · Cited by 43 · see citing works
Self-citationEsteban‐Medina, M., Peña-Chilet, M., Loucera, C., & Dopazo, J. (2019) · BMC Bioinformatics · doi:10.1186/s12859-019-2969-0 · Cited by 40 · see citing works
“COX enzymes have a role in response to oxidative stress, COX-1 is believed to play a constitutive housekeeping role [78] and its inhibition induce apoptosis and lead to Prostaglandin production induced by ionizing radiation [79].”
BackgroundCell death mechanisms and their roles in pregnancy related disorders
Kasture, V., Sahay, A. S., & Joshi, S. (2021) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2021.01.006 · Cited by 41 · see citing works
Vishweswaraiah, S., Swierkowska, J., Ratnamala, U., Mishra, N. K., Guda, C., Chettiar, S. S., Johar, K., Mrugacz, M., Karolak, J. A., Gajęcka, M., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-40299-x · Cited by 36 · see citing works
Szczukowski, Ł., Redzicka, A., Wiatrak, B., Krzyżak, E., Marciniak, A., Gębczak, K., Gębarowski, T., & Świątek, P. (2020) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2020.104035 · Cited by 35 · see citing works
Protocadherin 12 deficiency alters morphogenesis and transcriptional profile of the placenta
Rampon, C., Bouillot, S., Climescu-Haulica, A., Prandini, M., Cand, F., Vandenbrouck, Y., & Huber, P. (2008) · Physiological Genomics · doi:10.1152/physiolgenomics.00220.2007 · Cited by 34 · see citing works
“For example, Gja1 (CX43), Psg19, Mmp9, and Cox1 are solely or primarily expressed by glycogen cells (5, 6, 23, 36) and TIE1 and KDR are mainly located on the endothelial cell surface (11, 33).”
BackgroundSamudra, A. N., Dwyer, K. M., Selan, C., Freddi, S., Murray‐Segal, L., Nikpour, M., Hickey, M. J., Peter, K., Robson, S. C., Sashindranath, M., et al. (2017) · Journal of Autoimmunity · doi:10.1016/j.jaut.2017.10.009 · Cited by 34 · see citing works
Umekawa, T., Sugiyama, T., Kihira, T., 村林, 奈., Zhang, L., Nagao, K., Kamimoto, Y., Ma, N., Yodoi, J., & Sagawa, N. (2008) · Endocrinology · doi:10.1210/en.2007-1682 · Cited by 32 · see citing works
Wu, M., Zhao, A., Yan, X., Gao, H., Zhang, C., Liu, X., Luo, Q., Xie, F., Liu, S., & Shi, D. (2022) · eLife · doi:10.7554/elife.79939 · Cited by 30 · see citing works
Bevilacqua, E. M. A. F., Gomes, S. Z., Lorenzon, A. R., Hoshida, M. S., & Amarante-Paffaro, A. M. (2012) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2012.03.016 · Cited by 27 · see citing works
“ROS play important roles in normal placental development (Burdon et al., 2007; Raijmarkers et al., 2006), in contrast to the oxidative stress considered responsible for the pathophysiology of many diseases, including miscarriage, preeclampsia, intrauterine growth restriction and premature rupture of membranes (Burdon…”
BackgroundZuñiga, F. A., Ormazábal, V., Gutiérrez, N., Aguilera, V., Radojkovic, C., Veas, C., Escudero, C., Lamperti, L., & Aguayo, C. R. (2014) · BioMed Research International · doi:10.1155/2014/353616 · Cited by 26 · see citing works
Vidal, M. S., Richardson, L., Kammala, A. K., Kim, S., Lam, P. Y., Cherukuri, R., Thomas, T. J., Bettayeb, M., Han, A., Rusyn, I., et al. (2024) · Lab on a Chip · doi:10.1039/d3lc00998j · Cited by 24 · see citing works
Szczukowski, Ł., Krzyżak, E., Zborowska, A., Zając, P., Potyrak, K., Peregrym, K., Wiatrak, B., Marciniak, A., & Świątek, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249623 · Cited by 25 · see citing works
Szczukowski, Ł., Krzyżak, E., Wiatrak, B., Jawień, P., Marciniak, A., Kotynia, A., & Świątek, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011235 · Cited by 25 · see citing works
“According to many studies, the aforementioned processes often co-exist and potentiate one another [39,40].”
BackgroundReiter, R. J., Sharma, R., Chuffa, L. G. D. A., Zuccari, D. A. P. D. C., do Amaral, F. G., & Cipolla‐Neto, J. (2024) · Reproductive Toxicology · doi:10.1016/j.reprotox.2024.108534 · Cited by 21 · see citing works
Yao, Q. Z., Chen, L., Liang, Y., Sui, L., Guo, L., Zhou, J., Fan, K., Jing, J., Zhang, Y., & Yao, B. (2016) · Scientific Reports · doi:10.1038/srep25023 · Cited by 19 · see citing works
Adams, A. D., Guedj, F., & Bianchi, D. W. (2019) · Placenta · doi:10.1016/j.placenta.2019.10.002 · Cited by 18 · see citing works
Differences in Apoptotic Status in the Bovine Placentome between Spontaneous and Induced Parturition
Hirayama, H., Ushizawa, K., Takahashi, T., Sawai, K., Moriyasu, S., KAGEYAMA, S., Miura, R., Matsui, M., Fukuda, S., Naito, A., et al. (2012) · Journal of Reproduction and Development · doi:10.1262/jrd.2012-043 · Cited by 16 · see citing works
“In the murine placenta, apoptotic cells and the expression of caspase-3 (CASP3), one of the key executioners of apoptosis, showed temporal and spatial associations [7, 8].”
BackgroundZhang, Y., & Igwe, O. J. (2017) · International Immunopharmacology · doi:10.1016/j.intimp.2017.11.017 · Cited by 16 · see citing works
“For example, murine placenta, which experience oxidative stress during gestation, exhibited higher expression of COX-1 and COX-2 [45]. mPGES-1 is a perinuclear protein that is markedly induced by cytokines and growth factors as in the case of COX-2 [43].”
Suthar, H., Manea, T., Pak, D., Woodbury, M., Eick, S. M., Cathey, A. L., Watkins, D. J., Strakovsky, R. S., Ryva, B. A., Pennathur, S., et al. (2024) · Environmental Science & Technology · doi:10.1021/acs.est.4c00094 · Cited by 15 · see citing works
α-Solanine Causes Cellular Dysfunction of Human Trophoblast Cells via Apoptosis and Autophagy
Chen, Z., Li, C., Yuan, A., Gu, T., Zhang, F., Fan, X., Wu, X., Xiong, X., & Yang, Q. (2021) · Toxins · doi:10.3390/toxins13010067 · Cited by 15 · see citing works
“Malfunctioning of trophoblasts leads to inflammation [25], oxidative stress [26,27], apoptosis [28,29], and dysregulated angiogenesis [30].”
BackgroundThe Role of Autophagy in the Female Reproduction System: For Beginners to Experts in This Field
Nakashima, A., Furuta, A., Yamada, K., Yoshida‐Kawaguchi, M., Yamaki‐Ushijima, A., Yasuda, I., Ito, M., Yamashita, S., Tsuda, S., Yoneda, S., et al. (2023) · Biology · doi:10.3390/biology12030373 · Cited by 14 · see citing works
“The hypoxia-reoxygenation (H/R) model is well used for in vitro preeclamptic placental models because H/R poses ER and oxidative stress in trophoblasts [82,83].”
MethodMaternal diabetes impairs oxidative and inflammatory response in murine placenta
Saad, M. I., Abdelkhalek, T. M., Saleh, M. M., Haiba, M. M., Tawfik, S. H., & Kamel, M. A. E.-N. (2016) · SpringerPlus · doi:10.1186/s40064-016-2180-y · Cited by 14 · see citing works
Flip a coin: cell senescence at the maternal–fetal interface
Gong, G.-S., Muyayalo, K. P., Zhang, Y., Lin, X., & Liao, A. (2023) · Biology of Reproduction · doi:10.1093/biolre/ioad071 · Cited by 13 · see citing works
“Trophoblasts also experienced oxidative stress in rats and mice [95, 96].”
BackgroundNandi, A. A., Wadhwani, N. S., & Joshi, S. (2019) · BioFactors · doi:10.1002/biof.1510 · Cited by 13 · see citing works
Stereological study of the placental structure in abortion-prone mice model (CBA/J×DBA/2J)
Hosseini, M. S., Ali‐Hassanzadeh, M., Nadimi, E., Karbalay‐Doust, S., Noorafshan, A., & Gharesi‐Fard, B. (2020) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/j.aanat.2020.151508 · Cited by 13 · see citing works
Brown, J. L., Sones, J. L., Angulo, C. N., Abbott, K., Miller, A. D., Boehm, U., & Roberson, M. S. (2019) · Scientific Reports · doi:10.1038/s41598-019-45997-0 · Cited by 13 · see citing works
Yokoi, R., Hayashi, M., Tamura, T., Kobayashi, K., Kuroda, J., Kusama, H., KAGAMI, H., & Ono, T. (2008) · The Journal of Toxicological Sciences · doi:10.2131/jts.33.585 · Cited by 9 · see citing works
“Hypoxia-reoxygenation resulting in oxidative stress has been shown to be associated with the formation of hydroxynonenal, a marker of lipid peroxidation, in the mouse placenta on embryonic day 16 and thereafter but not on embryonic day 14 (Burdon et al., 2007).”
BackgroundInfluentialHepatotoxicity effect of short-term Bradykinin potentiating factor in cholestatic rats
Fahmy, S. R., Mohamed, A. S., Hosney, M., Issa, H. A., Hassanein, S. S., & Soliman, A. M. (2018) · Toxicology Letters · doi:10.1016/j.toxlet.2018.11.006 · Cited by 8 · see citing works
The expression of thioredoxin-1 in preterm delivery placenta
Song, J., Dong, X., Chen, Y., Chen, G., Hong, L. L., Nakamura, H., Yodoi, J., & Bai, J. (2012) · Redox Report · doi:10.1179/1351000212y.0000000021 · Cited by 7 · see citing works
Lavie, A., Dahan, M. H., Nu, T. N. T., Balayla, J., Gil, Y., Machado-Gédéon, A., Cui, Y., Shaul, J., & Volodarsky‐Perel, A. (2021) · Human Fertility · doi:10.1080/14647273.2021.1964102 · Cited by 6 · see citing works
Griffith, J. A., King, R. D., Dunn, A. C., Lewis, S. E., Maxwell, B. A., Nurkiewicz, T. R., Goldsmith, W. T., Kelley, E. E., & Bowdridge, E. C. (2023) · Advances in Redox Research · doi:10.1016/j.arres.2023.100090 · Cited by 6 · see citing works
“In a mouse model, oxidative stress increased close to term and the authors proposed that this played a physiologic role by increasing prostaglandin synthesis, some of which helped to induce parturition [25].”
BackgroundSignificance of the endothelium in the development of gestational complications
Safarovna, K. M., & Пахомова, Ж. Е. (2015) · Russian Bulletin of Obstetrician-Gynecologist · doi:10.17116/rosakush201515118-23 · Cited by 5 · see citing works
Inagaki, M., Nishimura, T., Akanuma, S., Nakanishi, T., Tachikawa, M., Tamai, I., Hosoya, K., Nakashima, E., & Tomi, M. (2017) · Placenta · doi:10.1016/j.placenta.2017.04.002 · Cited by 5 · see citing works
Paraoxonase 2 Protein Is Spatially Expressed in the Human Placenta and Selectively Reduced in Labour
Alwarfaly, S., Abdulsid, A., Hanretty, K. P., & Lyall, F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096754 · Cited by 4 · see citing works
“In vitro studies also suggest that hypoxiareoxygenation increases COX-2 which may in turn play a role in augmentation or even initiation of labour [26].”
BackgroundMorphological and morphometric evaluation of placenta in hypothyroid mothers
Kumari, S., Rani, A., Diwan, R., Srivastava, A., Mehta, V., & Rk, S. (2016) · Astrocyte · doi:10.4103/2349-0977.192708 · Cited by 4 · see citing works
“[9] Placental dysfunction is the central characteristic of all three of these complications of human pregnancy.[10-14] Any deviation in the placental morphology indicates fetal compromise during intrauterine life.”
BackgroundLi, S.-Y., Shang, T., Shu-juan, L. I., Rui, G.-H., & Qiu-ling, L. I. (2007) · Chinese Medical Journal · doi:10.1097/00029330-200708010-00011 · Cited by 4 · see citing works
Wang, J., Hua, G., Chen, J., Cui, K., Yang, Z., Han, D., Yang, X. Q., Dong, X., Ma, Y., Cai, G., et al. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01142-z · Cited by 3 · see citing works
“Interestingly, the high expression of the oxidative stress marker proteins COX2 [34] and glutathione peroxidyl/transferase in the MF group, again suggesting a strong oxidative stress state in the skin of MF lambs (Fig.”
BackgroundFerraz, T., Cardoso, L., Mohammadkhani, S., Bloise, E., & Connor, K. L. (2026) · American Journal of Reproductive Immunology · doi:10.1111/aji.70290 · Cited by 2 · see citing works
6, C. M. F. №., Evgenevna, P. Z., Safarovna, K. M., & 6, C. M. F. №. (2016) · The Bulletin of Contemporary Clinical Medicine · doi:10.20969/vskm.2016.9(1).51-57 · Cited by 2 · see citing works
Szczukowski, Ł., Maniewska, J., Wiatrak, B., Jawień, P., Krzyżak, E., Kotynia, A., Marciniak, A., Janeczek, M., & Redzicka, A. (2023) · Membranes · doi:10.3390/membranes13030349 · Cited by 1 · see citing works
“Therefore, drugs that have the ability to scavenge free radicals may play an important role in alleviating inflammation and could protect lipids and chromatin from oxidation [16,30,31,89,90].”
BackgroundCyclooxygenase 2 as a Marker of Early Pregnancy Loss in Cytomegalovirus Infection
Ishutina, N. A., Andrievskaya, I. A., & German, M. N. (2020) · Бюллетень Восточно-Сибирского научного центра Сибирского отделения Российской академии медицинских наук · doi:10.29413/abs.2020-5.3.1 · Cited by 1 · see citing works
Role of nuclear factor kappa beta, tumor necrosis factor α, and cyclooxygenase-2 in preterm labor
Riva'i, S. B., Darwin, E., Nasrul, E., & Effendi, J. S. (2015) · Medical Journal of Indonesia · doi:10.13181/mji.v23i4.1005 · Cited by 1 · see citing works
Untersuchungen zum Zellkommunikationsprotein Connexin31 in Trophoblast-Stammzellen aus Mus musculus
Graevendiek, T. (2009) · DuEPublico (University of Duisburg-Essen)
Andrievskaya, I. A., Ishutina, N. A., Dovzhikova, I. V., & Prihod'ko, N. (2020) · International Scientific Conference "System Analysis in Medicine" (SAM) · doi:10.12737/conferencearticle_5fe01d9c086109.30801383
Metabolomic Analysis of Serum and Placenta in PreeclampsiaPreprint
Dong, Y., Liu, X., Zhao, S., Zheng, Y., Li, C., Si, D., Chen, J., Wang, J., Chen, L., Hu, S., et al. (2020) · doi:10.21203/rs.3.rs-39243/v1
“The induction of the COX enzymes has been reported closely related to excessive oxidative stress in rat cytotrophoblast, spongiotrophoblast and glycogen cells and might be regulated through activation of the p38MAPK and the NF-κB transcription factor [44].”
BackgroundPlacental transport and metabolism
Dicke, J. M. (2021) · CRC Press eBooks · doi:10.1201/9781003222590-63
“In vitro studies using murine placenta subjected to oxidative stress through a process of hypoxia/ reoxygenation have demonstrated significant increases in the concentrations of cyclooxygenase, enzymes that stimulates PG production (22).”
PREECLAMPSIAAND STERILE INFLAMMATORY MOLECULES
Bhagat, S., Khan, M., & Khan, G. A. (2021) · International Journal of Environment and Health Sciences · doi:10.47062/1190.0301.04
The Clocks of Motivation: Rhythms of Molecular Restraints Originate Intentional Behaviors
Ferber, S. G. (2025) · Springer eBooks · doi:10.1007/978-3-031-89603-3_8
Glutathione depletion activates cGAS-STING signaling via oxidative stress in preeclampsia
Hu, S., Liu, W., Dong, Y., Wu, S. W., Zhao, S., Zheng, Y., Li, C., Si, D., Chen, J., Su, S., et al. (2026) · Molecular Immunology · doi:10.1016/j.molimm.2026.04.014
Katić, A., Himelreich-Perić, M., Krsnik, D., Petrina, P., Hohšteter, M., Žunec, S., Rašić, D., Micek, V., Neuberg, M., Kozina, G., et al. (2026) · Toxics · doi:10.3390/toxics14110955
- Authors
- Burdon, C., Mann, C., Cindrova-Davies, T., Ferguson-Smith, A. C., & Burton, G. J.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Burton, G.J.
- Venue
- Placenta
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 28
- Issue
- 7
- Pages
- 724-733
- ISSN
- 0143-4004 (ISSN-L)
- PMC
- PMC1895600
- OpenAlex
- W2013955956
- Cited by
- 71
- References
- 41
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 6 · 2022: 1 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 3 · 2014: 3 · 2013: 1 · 2012: 4
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Placenta (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (069027)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- placental oxidative stress, cyclooxygenase-1, cyclooxygenase-2, apoptosis, hypoxia/reoxygenation, 4-hydroxynonenal, trophoblast, glycogen cells, labyrinth zone, junctional zone, caspase-3, TUNEL, childbirth, placental development
- MeSH terms
- Aldehydes, Animals, Female, Mice, Inbred C57BL, Placenta, Pregnancy, Blotting, Western, Biomarkers, Up-Regulation, Apoptosis, Oxidative Stress, Mice, Cyclooxygenase 1, Cyclooxygenase 2, Caspase 3
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