Maternal nutrition is an important determinant of one-carbon metabolism that lies at the heart of intrauterine epigenetic programming. Exchange of nutrients and other vital molecules between the mother and fetus takes place across the placenta and hence may play direct role in fetal programming. Pre-eclampsia (PE) originates in the placenta and altered maternal nutrition may influence epigenetic patterns in the placenta, thereby affecting birth outcome. In the present study, we investigated the global DNA methylation levels in placentas of pre-eclampsia women (i.e., women delivering at term and those delivering preterm) and studied their associations with maternal blood pressure and birth outcome. Increased homocysteine and global DNA methylation levels were seen in the pre-eclampsia group (term and preterm PE) when compared with the normotensive group (p < 0.05). A positive association between global DNA methylation and systolic (p < 0.01) and diastolic (p < 0.05) blood pressure was seen in the term pre-eclampsia group, whereas there was no association with birth outcome. The study for the first time provides evidence for altered global DNA methylation patterns in pre-eclampsia placentas and its association with blood pressure. It is possible that increased homocysteine levels may be related to increased methylation in pre-eclampsia.
Get full access to this article
View all access options for this article.
References
1.
BönschD., LenzB., ReulbachU., KornhuberJ., BleichS.2004. Homocysteine associated genomic DNA hypermethylation in patients with chronic alcoholism. J Neural Transm, 111:1611–1616.
2.
BrombergA., LevineJ., NemetzB., BelmakerR.H., AgamG.2008. No association between global leukocyte DNA methylation and homocysteine levels in schizophrenia patients. Schizophr Res, 101:50–57.
3.
CastroR., RiveraI., StruysE.A., JansenE.E.W., RavascoP., CamiloM.E., BlomH.J., JakobC., Tavares de AlmeidaI.2003. Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clin Chem, 49:1292–1296.
4.
ChelbiS.T., MondonF., JammesH., BuffatC., MignotT.M., TostJ., BusatoF., GutI., RebourcetR., LaissueP., TsatsarisV., GoffinetF., RigourdV., CarbonneB., FerreF., VaimanD.2007. Expressional and epigenetic alterations of placental serine protease inhibitors: SERPINA3 is a potential marker of preeclampsia. Hypertension, 49:76–83.
5.
DangatK., MehendaleS., YadavH., KilariA., KulkarniA., TaralekarV., JoshiS.R.2010. Long chain polyunsaturated fatty acid composition of breast milk in pre-eclampsia mothers. Neonatology, 97:190–194.
6.
DetichN., HammS., JustG., KnoxJ.D., SzyfM.2003. The methyl donor S-adenosylmethionine inhibits active demethylation of DNA: a candidate novel mechanism for the pharmacological effects of S-adenosylmethionine. J Biol Chem, 278:20812–20820.
7.
DolinoyD.C., WeidmanJ.R., JirtleR.L.2007. Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol, 23:297–307.
FukeC., ShimabukuroM., PetronisA., SugimotoJ., OdaT., MiuraK., MiyazakiT., OguraC., OkazakiY., JinnoY.2004. Age related changes in 5-methyl cytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet, 68:196–204.
10.
Gama-SosaM.A., MidgettR.M., SlagelV.A., GithensS., KuoK.C., GehrkeC.W., EhrlichM.1983. Tissue-specific differences in DNA methylation in various mammals. Biochim Biophys Acta, 740:212–219.
11.
GuvenM.A., CoskunA., ErtasI.E., AralM., ZencirciB., OksuzH.2009. Association of maternal serum CRP, IL-6, TNF-alpha, homocysteine, folic acid and vitamin B12 levels with the severity of preeclampsia and fetal birth weight. Hypertens. Pregnancy, 28:190–200.
12.
KaleA., NaphadeN., SapkaleS., KamarajuM., PillaiA., JoshiS., MahadikS.2010. Reduced folic acid, vitamin B12 and docosahexaenoic acid and increased homocysteine and cortisol in never-medicated schizophrenia patients: implications for altered one-carbon metabolism. Psychiatry Res, 175:47–53.
13.
KulkarniA., MehendaleS., YadavH., KilariA., TaralekarV., JoshiS.2010. Circulating angiogenic factors and their association with birth outcomes in pre-eclampsia. Hypertens Res, 33:561–567.
LiE.2002. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet, 3:662–673.
16.
LiuC., WangQ., GuoH., XiaM., YuanQ., HuY., ZhuH., HouM., MaJ., TangZ., LingW.2008. Plasma S-adenosylhomocysteine is a better biomarker of atherosclerosis than homocysteine in apolipoprotein E-deficient mice fed high dietary methionine. J Nutr, 138:311–315.
17.
MaccaniM.A., MarsitC.J.2009. Epigenetics in the placenta. Am J Reprod Immunol, 62:78–89.
18.
MakedosG., PapanicolaouA., HitoglouA., KalogiannidisI., MakedosA., VraziotiV., GoutzioulisM.2007. Homocysteine, folic acid and B12 serum levels in pregnancy complicated with preeclampsia. Arch Gynecol Obstet, 275:121–124.
19.
MehendaleS., KilariA., DangatK., TaralekarV., MahadikS., JoshiS.2008. Fatty acids, antioxidants, and oxidative stress in pre-eclampsia. Int J Gynaecol Obstet, 100:234–238.
20.
MüllerH.M., IvarssonL., SchröcksnadelH., FieglH., WidschwendterA., GoebelG., Kilga-NoglerS., PhiladelphyH., GütterW., MarthC., WidschwendterM.2004. DNA methylation changes in sera of women in early pregnancy are similar to those in advanced breast cancer patients. Clin Chem, 50:1065–1068.
21.
MyattL.2006. Placental adaptive responses and fetal programming. J Physiol, 572:25–30.
22.
RazinA., KafriT.1994. DNA methylation from embryo to adult. Prog Nucleic Acid Res Mol Biol, 48:53–81.
23.
ReikW., ConstânciaM., FowdenA., AndersonN., DeanW., Ferguson-SmithA., TyckoB., SibleyC.2003. Regulation of supply and demand for maternal nutrients in mammals by imprinted genes. J Physiol, 547.1:35–44.
24.
RobertsJ.M., CatovJ.M.2008. Preeclampsia more than 1 disease or is it? [Letter]Hypertension, 51:989–990.
25.
SharmaP., KumarJ., GargG., KumarA., PatowaryA., KarthikeyanG., RamakrishnanL., BrahmachariV., SenguptaS.2008. Detection of altered global DNA methylation in coronary artery disease patients. DNA Cell Biol, 27:357–365.
26.
SinghU., GuptaH.P., SinghR.K., ShuklaM., SinghR., MehrotraS.S., PrasadS.2008. A study of changes in homocysteine levels during normal pregnancy and pre-eclampsia. J Indian Med Assoc, 106:503–505.
27.
SymondsM.E., SebertS.P., HyattM.A., BudgeH.2009. Nutritional programming of the metabolic syndrome. Nat Rev Endocrinol, 5:604–610.
28.
TroisiR., BraekkeK., HarsemN.K., HyerM., HooverR.N., StaffA.C.2008. Blood pressure augmentation and maternal circulating concentrations of angiogenic factors at delivery in preeclampsia and uncomplicated pregnancies. Am J Obstet Gynecol, 199:653.e1–653.10.
29.
UnterbergerA., SzyfM., NathanielszP.W., CoxL.A.2009. Organ and gestational age effects of maternal nutrient restriction on global methylation in fetal baboons. J Med Primatol, 38:219–227.
30.
UthusE.O., AndersonC.M.2010. Epigenetic placental programming of preeclampsia. FASEB J, 24:344.2(abstract).
31.
WangJ., ZhaoF., WuY., LiuR., MuY.2010. Quantitative detection of the hypermethylated RASSF1A gene in maternal plasma of pre-eclampsia. Chin J Med Genet, 27:73–76.
32.
WaterlandR.A., JirtleR.L.2004. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition, 20:63–68.
33.
YiP., MelnykS., PogribnaM., PogribnyI.P., HineR.J, JamesS.J.2000. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem, 275:29318–29323.
34.
YuenR.K.C., PeñaherreraM.S., von DadelszenP., McFaddenD.E., RobinsonW.P.2010. DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia. Eur J Hum Genet, May5[Epub ahead of print].
35.
ZighettiM.L., ChantarangkulV., TripodiA., MannucciP.M., CattaneoM.2002. Determination of total homocysteine in plasma: comparison of the Abbott IMx immunoassay with high performance liquid chromatography. Haematologica, 87:89–94.
