In Vivo and In Vitro Evidence for Placental DNA Damage in Preeclampsia

Serkalem Tadesse,Felice Arcuri,Errol R Norwitz,Tianmeng Luo,Dawit Kidane,Nicholas G Norwitz,Seth Guller,Paolo Toti,Hai-Yan Lin

doi:10.1371/journal.pone.0086791

Serkalem Tadesse, Felice Arcuri + Show 7 more

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https://doi.org/10.1371/journal.pone.0086791

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Abstract

Preeclampsia (PE) is an idiopathic multisystem disease affecting 5–7% of pregnant women. Placental oxidative stress is a characteristic feature of PE and occurs when the production of reactive oxygen species (ROS) within the placenta overwhelms the intrinsic anti-oxidant defenses. We hypothesize that excessive oxidative DNA damage at the fetal-maternal interface coupled with a defective DNA damage/repair response is causally related to PE. Here we demonstrate that γH2AX (a sensitive marker of DNA damage) is expressed in the maternal decidua but not trophoblast of normal placentas, and that expression is significantly higher in PE placental tissues in vivo. Using primary in vitro cultures of maternal decidual stromal cells (DSCs) and fetal cytotrophoblast cells (CTs), we show an increase in γH2AX foci in DSCs cultured with vs without H2O2 (70.6% vs 11.6%; P<0.0001) or under hypoxia-reperfusion vs normoxia (20- vs 3-fold; P = 0.01); no foci were seen in CTs. We further demonstrate that Base Excision Repair (BER) intermediates are significantly increased in DSCs (not CTs) under these same conditions. Our data show that DNA damage is significantly more common in PE placentas, and that this DNA damage is localized to the maternal and not fetal side of the placenta. CTs may be selectively resistant to DNA damage in an effort to protect the fetus.

Highlights

Preeclampsia (PE) is an idiopathic multisystem disease affecting 5–7% of pregnant women
While low levels of cH2AX immunoreactivity was detected in control tissues (Fig. 1A–1D), high levels were evident in PE placentas and appeared to be localized to the maternal cells of the decidua, which stained positive for vimentin (Fig. 1C and 1G)
Results showed a significant increase in the number of cells staining positive for cH2AX when decidual stromal cells (DSCs) cells were treated as opposed to untreated with H2O2 (70.6% vs 11.6%, respectively; P,0.0001) (Fig. 2A–2H and Fig. 2Q)

Summary

Introduction

Preeclampsia (PE) is an idiopathic multisystem disease affecting 5–7% of pregnant women. It is characterized clinically by newonset hypertension and proteinuria after 20 weeks of gestation [1]. Mitochondrial superoxide anion (O22) production is a critical source of oxidative stress within the placenta, and contributes to the overall increase in maternal and placental lipid peroxidation seen in pregnancy [6,7,8]. PE pregnancies are characterized by an imbalance in these processes leading to an increase in oxidative stress [6,7,8].

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