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

Tadesse, Serkalem; Kidane, Dawit; Guller, Seth; Luo, Tianmeng; Norwitz, Nicholas G.; Arcuri, Felice; Toti, Paolo; Norwitz, Errol R.

doi:10.1371/journal.pone.0086791

Cited by 31 publications

(27 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genomic instability is not an area of cellular dysfunction that has been extensively studied in the placenta. However, there is compelling evidence that DNA damage contributes to placental pathologies, including pre‐eclampsia (Fujimaki et al, ; Hilali et al, ; Tadesse et al, ). This DNA damage is characterized by increased DNA double‐stranded breaks, as characterized by increased levels of γ‐H2AX foci formation (Tadesse et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…However, there is compelling evidence that DNA damage contributes to placental pathologies, including pre-eclampsia (Fujimaki et al, 2011;Hilali et al, 2013;Tadesse et al, 2014). This DNA damage is characterized by increased DNA double-stranded breaks, as characterized by increased levels of γ-H2AX foci formation (Tadesse et al, 2014). Future studies will revolve around understanding how BRCA1 influences DNA repair in placental cells.…”

mentioning

confidence: 99%

See 1 more Smart Citation

BRCA1 regulates HMGA2 levels in the Swan71 trophoblast cell line

West

Russ

Bouma

et al. 2019

Molecular Reproduction Devel

View full text Add to dashboard Cite

During early placental development, tumor suppressors and oncogenes work synergistically to regulate cell proliferation and differentiation in a restrained manner compared with the uncontrollable growth in cancer. One example of this partnership is the regulation of the oncofetal protein HMGA2 by BRCA1. BRCA1 forms a repressor complex with ZNF350 and CtIP to bind to the promoter of HMGA2, preventing transcription. Chromatin immunoprecipitation determined BRCA1 forms this repressor complex in human trophoblast cells, suggesting a role in the placenta. Furthermore, miR‐182 has been shown to target BRCA1 mRNA in ovarian cancer cells, blocking the formation of the BRCA1 repressor complex and allowing increased transcription of HMGA2. miR‐182 was one of the first miRNAs described as elevated in the serum and placentas of preeclamptic women. Therefore, we hypothesized that BRCA1 is essential for normal trophoblast cell development. We used CRISPR‐Cas9 genome editing and miR‐182 overexpression to decrease BRCA1 protein in the Swan71 cell line. HMGA2 was significantly increased in the BRCA1 KO and miR‐182 overexpressing cells compared to controls. We also determined that BRCA1 repressor complex binding to HMGA2 was significantly reduced in BRCA1 KO and miR‐182 overexpressing cells compared with controls, leading us to conclude that increased HMGA2 was because of decreased binding of the BRCA1 repressor complex. Finally, we found that the caspase activity was significantly higher in BRCA1 KO and miR‐182 overexpressing cells suggesting an increased amount of apoptosis. These data suggest that BRCA1 is an important regulator of the oncofetal protein HMGA2 and promotes cell survival in human placental cells.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

BRCA1 regulates HMGA2 levels in the Swan71 trophoblast cell line

West

Russ

Bouma

et al. 2019

Molecular Reproduction Devel

View full text Add to dashboard Cite

show abstract

“…Both in vivo and in vitro [92] studies on placentas from PE patients have shown significantly higher expression of γH2AX vs. normotensive controls and they appear to be localized to the maternal cells of the decidua. A statistically significant hypomethylation of CpG sites in maternal systemic blood vessels has been shown in preeclamptic women compared to controls.…”

Section: Soluble Endoglin (Seng)mentioning

confidence: 99%

Prediction of Preeclampsia-Bench to Bedside

et al. 2014

View full text Add to dashboard Cite

Hypertensive disorders of pregnancy (HDP) constitute the most common medical condition seen during gestation, effecting 1 in 10 pregnancies in the USA. Traditionally, preeclampsia (PE) is defined as a new onset of hypertension and either proteinuria or end-organ dysfunction after 20 weeks of gestation in a previously normotensive woman. Preeclampsia is a potentially life-threatening condition with widespread underlying endothelial dysfunction, and accompanying inflammation, vasoconstriction, and platelet activation. Women with preeclampsia are at an increased risk for life-threatening complications and progression to eclampsia. Worldwide, 10 to 15 % of maternal deaths are from preeclampsia and related complications. Traditionally, diagnosis of preeclampsia is made based upon presence of risk factors and clinical criteria. Diagnosis is challenging in asymptomatic women early in pregnancy as well as in nulliparous women as they lack obstetric history; however, it is well known that women with previous preeclampsia have a 14.7 % risk of the condition in the second pregnancy. Prediction of those at risk and early diagnosis is crucial to enable close surveillance of high-risk women in order to improve maternal and fetal outcomes. There has been much advance in our understanding of the pathogenesis of PE and in the field of angiogenic markers. However, no one test meets the criteria for a good biomarker. A multiparametric approach appears to be optimal as we await newer systems biology approaches to give us better insight into the pathogenesis of the disease.

show abstract

“…Normally, the increase in the levels of oxidative stress induced by pregnancy is promptly managed. It has been proposed that tissue damage secondary to unmanaged placental oxidative stress occurs when intrinsic mechanisms for management of oxidative stress cannot cope with the rates of placental production of ROS [106]. Increased levels of oxidative stress measured early in pregnancy (from 16 to 20 w.g.)…”

Section: Role Of the Individual Repair Capacity In The Constitution Omentioning

confidence: 99%

“…have been shown to reliably predict the development of preeclampsia later [107]. Elevated levels of products of lipid peroxidation, 8-hydroxydeoxyguanosine (8-OH-dG), phosphorylated H2AX (both markers for the presence of DNA damage) and intermediates signifying ongoing DNA repair of oxidative damage have been repeatedly demonstrated in placentas from pregnancies complicated by preeclampsia compared to placentas from normal pregnancies [104][105][106]108].…”

Section: Role Of the Individual Repair Capacity In The Constitution Omentioning

confidence: 99%

Reproductive outcomes in pregnant women aged 35 or older: the role of individual repair capacity

Petkova¹,

Dimitrova²,

Zhelev³

et al. 2015

Biodiscovery

View full text Add to dashboard Cite

Abbreviations: 8-OH-dG -8-hydroxydeoxyguanosine, AMA -advanced maternal age, AR -assisted reproduction, BER -base excision repair, CDC -US Centre for disease prevention and control, DIC -disseminated intravascular coagulation, DS -Down syndrome, HELLP -haemolysis/elevated liver enzymes/low platelets, ICSI -intracytoplasmic sperm injection, IRC -individual repair capacity, IUGR -intrauterine growth restriction, IUI -intrauterine insemination, IVF -in vitro fertilisation, LIF -leukaemia inhibitory factor, NER -nucleotide excision repair, PCOS -polycystic ovary syndrome, PIH -pregnancy-induced hypertension, ROS -reactive oxygen species, TTD -trichothiodystrophy, w.g. -weeks of gestation, WHO -World Health Organisation, XP -xeroderma pigmentosum. AbstractAt present, childbirth is being progressively postponed until later age. Women aged 35 or older may have to wait longer to conceive than younger women and are more likely to be referred to fertility evaluations, but in a significant proportion a spontaneous conception would be achieved in the timeframe typical of younger women. Pregnancies where mothers are ≥ 35 are associated with more risks for pregnancy loss, chromosomal disease, pregnancy-associated complications, prematurity and low birthweight. These concerns, however, are not uncommon in younger women as well. This puts forward the question whether advanced age per se is the underlying cause for the increased risk for adverse outcomes in older pregnant women, or whether there might be other factors that account for it but do not radically worsen the prospects for favourable outcomes. The individual risks associated with childbirth late in life may stem from maternal genetic background rather than being a simple function of age. There is plenty of preliminary evidence that individual capacity for identification and repair of DNA damage may constitute a major factor in female fertility and fecundity. Subtle deficiencies in the repair capacity may have little to no importance in younger pregnant women but may make a significant difference in older women. The outcomes of pregnancies in women >35 are largely dependent on the prepregnancy health status and the quality of antenatal care, and may not be dramatically different from outcomes in younger women.

show abstract

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

Cited by 31 publications

References 41 publications

BRCA1 regulates HMGA2 levels in the Swan71 trophoblast cell line

BRCA1 regulates HMGA2 levels in the Swan71 trophoblast cell line

Prediction of Preeclampsia-Bench to Bedside

Reproductive outcomes in pregnant women aged 35 or older: the role of individual repair capacity

Contact Info

Product

Resources

About