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Placenta. 2018 Aug;68:15-22. doi: 10.1016/j.placenta.2018.06.307. Epub 2018 Jun 19.

Evidence of oxidative stress-induced senescence in mature, post-mature and pathological human placentas.

Author information

1
Centre for Trophoblast Research, University of Cambridge, UK. Electronic address: tc269@cam.ac.uk.
2
Centre for Trophoblast Research, University of Cambridge, UK; Francis Crick Institute, London, UK.
3
Maternal and Fetal Health Research Centre Division of Developmental Biology & Medicine School of Medical Sciences Faculty of Biology, Medicine and Health University of Manchester, Manchester Academic Health Science Centre, St Mary's Hospital Oxford Road Manchester M13 9 WL, UK.
4
Mount Sinai Hospital, University of Toronto, Canada.
5
Centre for Trophoblast Research, University of Cambridge, UK.

Abstract

INTRODUCTION:

Premature ageing has been implicated in placental dysfunction. Senescence can be activated by oxidative stress, a key intermediary in the pathophysiology of pre-eclampsia. We examined senescence markers across normal gestation, and in pathological and post-mature pregnancies. Inducers of oxidative stress were used to mimic senescence changes in term explants.

METHODS:

Placental samples were collected with ethical approval and informed consent: first and second trimester samples from surgical terminations; term and pre-term controls, and early-onset pre-eclampsia samples from caesarean deliveries. Paraffin and EM blocks of post-mature placentas were from an archival collection. Term explants were subjected to hypoxia-reoxygenation (HR) or hydrogen peroxide (H2O2).

RESULTS:

p21 was increased significantly in term homogenates compared to first and second trimester samples, and was significantly higher in PE compared to term controls. Immunostaining revealed nuclear localisation of p21 and phosphorylated histone γH2AX in syncytiotrophoblast, with abundant foci in pathological and post-mature placentas. Abnormal nuclear appearances were observed in post-mature placentas. Sudan-Black-B staining demonstrated abundant lipofuscin, an aggregate of oxidised proteins, lipids and metals, in post-mature and pathological placentas. The percentage of nuclei positive for 8-hydroxy-2'-deoxy-guanosine, a marker of oxidised DNA/RNA, was increased in pathological placentas compared to age-matched controls. These changes could be mimicked by challenge with HR or H2O2.

DISCUSSION:

Senescence markers increase in normal placentas with gestational age, and are exaggerated in post-mature and pathological cases. Oxidative stress triggers equivalent changes in explants, and may precipitate senescence in vivo. The consequent pro-inflammatory senescence-associated secretory phenotype may contribute to the pathophysiology of pre-eclampsia.

KEYWORDS:

Oxidative stress; Senescence; Syncytiotrophoblast

PMID:
30055665
PMCID:
PMC6083404
DOI:
10.1016/j.placenta.2018.06.307
[Indexed for MEDLINE]
Free PMC Article

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