Lower S-adenosylmethionine levels and DNA hypomethylation of placental growth factor (PlGF) in placental tissue of early-onset preeclampsia-complicated pregnancies

Abstract

IntroductionThe pathophysiology of preeclampsia is largely unknown. Serum placental induced growth factor (PlGF) levels are decreased during second trimester pregnancy. Aberrant DNA methylation is suggested to be involved in the etiology of preeclampsia (PE). We hypothesize that DNA methylation is altered in PE placentas determined the methylation index by measuring placental S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels. In addition, we assessed global DNA methylation status by long-interspersed nuclear element-1 (LINE-1) and DNA methylation status of the PlGF gene.MethodsPlacental tissue of 11 early onset PE (EOPE), 11 late onset PE (LOPE) and 60 controls consisting of 25 uncomplicated controls 20 fetal growth restriction (FGR) and 15 preterm births (PTB) controls was collected from a nested case-control study of The Rotterdam Periconceptional Cohort. RNA and DNA was isolated from placental tissue and DNA was treated with sodium bisulfite. SAM and SAH levels were measured by LC-ESI-MS/MS. Methylation of LINE-1 and PlGF genes was analyzed by Sequenom Epityper and. mRNA expression of PlGF was assessed with qPCR. Differences were assessed by analysis of covariance (ANCOVA) corrected for gestational age and birth weight.ResultsPlacental SAM levels were significantly lower in placental tissue of EOPE pregnancies compared to PTB controls (mean difference -240 ± 71.4 nmol/g protein, P = 0.01). PlGF DNA methylation was decreased in placental tissue of EOPE cases versus LOPE (mean difference -17.4 ± 5.1%, P = 0.01), uncomplicated controls (mean difference -23.4 ± 5.4%%, P <0.001), FGR controls (mean difference -17.9 ± 4.6%, P = 0.002) and PTB controls (mean difference -11.3 ± 3.8% P = 0.04). No significant differences were observed in SAH, SAM:SAH ratio, LINE-1 DNA methylation and PlGF mRNA expression between groups.DiscussionThe hypomethylation state of the placenta in EOPE, which is reflected by lower SAM and PlGF DNA hypomethylation underlines the possible role of placental DNA hypomethylation in the pathophysiology of EOPE, which needs further investigation.

Prenatal Hyperhomocysteinemia Induces Glial Activation and Alters Neuroinflammatory Marker Expression in Infant Rat Hippocampus

“…The most studied mechanisms of the neurotoxic action of Hcy include the development of oxidative stress under its influence [ 64 , 67 , 68 ] and excitotoxic effect due to structural similarity to glutamate [ 69 , 70 ]. However, recently, the essential role of HHC in epigenetic modifications associated with methylation reactions, primarily DNA methylation, has been actively studied [ 71 , 72 , 73 , 74 , 75 ]. Chronic elevation in Hcy level leads to a parallel increase in intracellular S-adenosyl-Hcy (SAH) with a strong inhibition of DNA methyltransferases.…”

Mechanisms of Key Innate Immune Cells in Early- and Late-Onset Preeclampsia

“…Interventionist care involves early delivery to minimize serious maternal and fetal complications. Expectant care provides relief from symptoms, such as reducing blood pressure with antihypertensive therapy and the use of magnesium sulfate as anticonvulsant therapy ( 2 , 15 , 16 ). Evidence suggests that there is no clear difference between an expectant or interventionist care approach for preeclampsia with severe features ( 14 ).…”

No Effect of Diet-Induced Mild Hyperhomocysteinemia on Vascular Methylating Capacity, Atherosclerosis Progression, and Specific Histone Methylation

“…SAM and SAH levels were measured in plasma (after 8 weeks on each diet) and in aortic lysates (at the end point) using a liquid chromatography tandem-mass spectrometry (LC-MS/MS) method after the use of solid-phase extraction columns according to an adapted method of Gellekink et al [25], and as previously described [26]. The stability of SAM and SAH in plasma was shown to be 100% if samples were stored immediately at −80 • C [23].…”