In vivo and in vitro evidence for placental DNA damage in preeclampsia

PLoS One. 2014 Jan 22;9(1):e86791. doi: 10.1371/journal.pone.0086791. eCollection 2014.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analysis of Variance
  • Blotting, Western
  • Cell Nucleus / metabolism
  • DNA Damage / genetics*
  • Decidua / cytology*
  • Decidua / pathology*
  • Female
  • Histones / immunology
  • Histones / metabolism
  • Humans
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Microscopy, Confocal
  • Pre-Eclampsia / genetics
  • Pre-Eclampsia / pathology*
  • Pregnancy
  • Reactive Oxygen Species / metabolism
  • Stromal Cells / metabolism
  • Trophoblasts / metabolism

Substances

  • H2AX protein, human
  • Histones
  • Reactive Oxygen Species

Grants and funding

This work was supported in part by the NIH/NICHD-sponsored Reproductive Scientist Development Program (to ERN) and March of Dimes (21-FY05-1250 to ERN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.