In vivo and in vitro evidence for placental DNA damage in preeclampsia.
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.
Department of Obstetrics & Gynecology, Tufts Medical Center, Boston, Massachusetts, United States of America ; Mother Infant Research Institute (MIRI), Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Serkalem
S
Tadesse
Department of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Dawit
D
Kidane
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Seth
S
Guller
Mother Infant Research Institute (MIRI), Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Tianmeng
T
Luo
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Nicholas G
NG
Norwitz
Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Felice
F
Arcuri
Department of Medical Biotechnologies, University of Siena, Siena, Italy.
Paolo
P
Toti
Department of Obstetrics & Gynecology, Tufts Medical Center, Boston, Massachusetts, United States of America ; Mother Infant Research Institute (MIRI), Tufts University School of Medicine, Boston, Massachusetts, United States of America.
Errol R
ER
Norwitz
D000328:Adult; D000704:Analysis of Variance; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D003656:Decidua / Q000166:cytology* / Q000473:pathology*; D005260:Female; D006657:Histones / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D011225:Pre-Eclampsia / Q000235:genetics / Q000473:pathology*; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism
C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species