Histochemistry and Cell Biology

, Volume 146, Issue 2, pp 191–204 | Cite as

Placental aging and oxidation damage in a tissue micro-array model: an immunohistochemistry study

  • Ambrogio P. LonderoEmail author
  • Maria Orsaria
  • Stefania Marzinotto
  • Tiziana Grassi
  • Arrigo Fruscalzo
  • Angelo Calcagno
  • Serena Bertozzi
  • Nastassia Nardini
  • Enrica Stella
  • Ralph J. Lellé
  • Lorenza Driul
  • Gianluca Tell
  • Laura Mariuzzi
Original Paper


To evaluate the expression of markers correlated with cellular senescence and DNA damage (8-hydroxy-2′-deoxy-guanosine (8-OHdG), p53, p21, APE1/Ref-1 (APE1), interleukin (IL-6 and IL-8) in placentas from healthy and pathologic pregnancies. This retrospective study considered a placental tissue micro-array containing 92 controls from different gestational ages and 158 pathological cases including preeclampsia (PE), HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), small for gestational age (SGA) fetuses, and intrauterine growth restriction (IUGR) occurring at different gestational ages. In this study, we demonstrated a significant influence of gestational age on the expression in the trophoblast of 8-OHdG, p53, p21, APE1, and IL-6. In placentas of cases affected by PE, HELLP, or IUGR, there was an increased expression of 8-OHdG, p53, APE1, and IL-6 compared to controls (only IL-8 was significantly decreased in cases). In both groups of pathology between 22- and 34-week gestation and after 34-week gestation, APE1 levels were higher in the trophoblast of women affected by hypertensive disorders of pregnancy than women carrying an IUGR fetus. The cytoplasmic expression of 8-OHdG was increased in placentas in IUGR cases compared to PE or HELLP pregnancies. In cases after 34-week gestation, p21 was higher in SGA and IUGR than in controls and late PE. Moreover, p53 was increased after 34-week gestation in IUGR pregnancies. Placentas from pathological pregnancies had an altered expression of 8-OHdG, p53, p21, APE1, IL-6, and IL-8. The alterations of intracellular pathways involving these elements may be the cause or the consequence of placental dysfunction, but in any case reflect an impaired placental function, possibly due to increased aging velocity in pathologic cases.


8-OHdG p53 p21 APE1/Ref-1 IL-6 IL-8 Placenta Preeclampsia IUGR 







APE1/Ref-1 (apurinic apyrimidinic endonuclease redox effector factor-1)


Base excision repair


Body mass index


Deoxyribonucleic acid


Hemolysis, elevated liver enzymes, low platelet count






Intrauterine growth restriction


Messenger ribonucleic acid




Ribonucleic acid


Senescence-associated secretory phenotype


Small for gestational age



We are grateful to Eilidh PJ McIntosh for her suggestions on the style and composition of our English. We are grateful to Vito D’Aietti for his precious help. We are grateful to Matteo De Luca for the technical assistance in realizing TMA and Marta Forgiarini and Magdalena Marciniak for technical support. We are also grateful to Prof. Diego Marchesoni, Prof. Carlo Alberto Beltrami, Prof. Carla Di Loreto, Prof. Dr. med. Walter Klockenbusch, and Prof. Gabriele Köhler for their help and suggestions. Furthermore, this research is based on the Ph.D. dissertation of Dr Ambrogio P Londero that took place in the University of Udine.

Authors’ contribution

APL, MO, TG, SM, AF, SB, NN, ES, and LM made substantial contributions to conception and design or acquisition of data or to analysis and interpretation of data. APL, MO, AC, SM, AF, SB, NN, LD, GT, RJL, and LM were involved in drafting the article or revising it critically for important intellectual content. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interests

The authors declare that they have no potential conflicts of interest relevant to this article. This study had no financial support.

Supplementary material

418_2016_1435_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 14 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ambrogio P. Londero
    • 1
    • 2
    Email author
  • Maria Orsaria
    • 3
  • Stefania Marzinotto
    • 3
  • Tiziana Grassi
    • 1
  • Arrigo Fruscalzo
    • 4
    • 5
  • Angelo Calcagno
    • 1
  • Serena Bertozzi
    • 6
  • Nastassia Nardini
    • 3
  • Enrica Stella
    • 1
  • Ralph J. Lellé
    • 5
  • Lorenza Driul
    • 1
  • Gianluca Tell
    • 3
  • Laura Mariuzzi
    • 3
  1. 1.Clinic of Obstetrics and Gynecology, Deparment of Experimental Clinical and Medical ScienceUniversity of UdineUdineItaly
  2. 2.Unit of Obstetrics and GynecologyS. Polo HospitalMonfalconeItaly
  3. 3.Department of Medical and Biological SciencesUniversity of UdineUdineItaly
  4. 4.Frauenklinik, St Franziskus HospitalMünsterGermany
  5. 5.Clinic of Obstetrics and Gynecology and Institute of PathologyUniversity Hospital of MünsterMünsterGermany
  6. 6.Department of Surgical OncologyIRCCS CROAvianoItaly

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