The nuclear receptor estrogen receptor α (ERα) is one of the key players in energy balance, insulin resistance, and trophoblast differentiation. We tested the hypothesis that gestational diabetes mellitus (GDM) alters expression of placental ERα in a cell type-specific manner and that this regulation may involve epigenetic changes.
Study Design:
Expression of ERα was analyzed by immunohistochemistry using the semiquantitative immunoreactive score in 80 placentas (40 GDM/40 controls). Quantitative real-time polymerase chain reaction (PCR) measured ERα messenger RNA (mRNA) in decidual tissue. Methylation-specific PCR was performed to analyze cytosine-phosphatidyl-guanine-island methylation of the ERα promoter.
Results:
Expression of ERα protein is upregulated (P = .011) in GDM in extravillous trophoblasts but not in syncytiotrophoblast. Gestational diabetes mellitus downregulated ERα in decidual vessels only in pregnancies with male but not female fetuses. Furthermore, mRNA of the ERα encoding gene estrogen receptor gene 1 (ESR1) was increased (+1.77 fold) in GDM decidua when compared to controls (P = .024). In parallel, the promoter of ESR1 was methylated only in decidua of healthy control individuals but not in GDM.
Conclusion:
Gestational diabetes mellitus affects expression of placental ERα in a cell type-dependent way, on epigenetic level. These data link GDM with epigenetic deregulations of ERα expression and open new insights into the intrauterine programming hypothesis of GDM.
RoperoABAlonso-MagdalenaPQuesadaINadalA. The role of estrogen receptors in the control of energy and glucose homeostasis. Steroids. 2008;73(9-10):874–879.
2.
BarrosRPMachadoUFGustafssonJA. Estrogen receptors: new players in diabetes mellitus. Trends Mol Med. 2006;12(9):425–431.
3.
TakedaKTodaKSaibaraT. Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol. 2003;176(2):237–246.
4.
HeinePATaylorJAIwamotoGALubahnDBCookePS. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci U S A. 2000;97(23):12729–12734.
5.
BarrosRPGustafssonJA. Estrogen receptors and the metabolic network. Cell Metab. 2011;14(3):289–299.
6.
GambinoYPMaymoJLPerez PerezACalvoJCSanchez-MargaletVVaroneCL. Elsevier Trophoblast Research Award lecture: Molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression. Placenta. 2012;33 suppl:S63–S70.
7.
MetzgerBEBuchananTACoustanDR. Summary and recommendations of the fifth international workshop-conference on gestational diabetes mellitus. Diabetes Care. 2007;30(suppl 2
):S251–S260.
8.
SacksDBArnoldMBakrisGL. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clin Chem. 2011;57(6):e1–e47.
SchwartzR. Hyperinsulinemia and macrosomia. N Engl J Med. 1990;323(5):340–342.
11.
HawdonJM. Babies born after diabetes in pregnancy: what are the short- and long-term risks and how can we minimise them?Best Pract Res Clin Obstet Gynaecol. 2011;25(1):91–104.
12.
Barnes-PowellLL. Infants of diabetic mothers: the effects of hyperglycemia on the fetus and neonate. Neonatal Netw. 2007;26(5):283–290.
ClausenTDMathiesenERHansenT. Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 diabetes. J Clin Endocrinol Metab. 2009;94(7):2464–2470.
15.
MaccaniMAMarsitCJ. Epigenetics in the placenta. Am J Reprod Immunol. 2009;62(2):78–89.
16.
WeberMHellmannIStadlerMB. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet. 2007;39(4):457–466.
17.
JaenischRBirdA. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33 suppl:245–254.
18.
BouchardLHivertMFGuaySPSt-PierreJPerronPBrissonD. Placental adiponectin gene DNA methylation levels are associated with mothers’ blood glucose concentration. Diabetes. 2012;61(5):1272–1280.
19.
JonesLHamiltonAJVoinnetOThomasCLMauleAJBaulcombeDC. RNA-DNA interactions and DNA methylation in post-transcriptional gene silencing. Plant Cell. 1999;11(12):2291–2301.
20.
TurnerBM. Defining an epigenetic code. Nat Cell Biol. 2007;9(1):2–6.
21.
BanisterCEKoestlerDCMaccaniMAPadburyJFHousemanEAMarsitCJ. Infant growth restriction is associated with distinct patterns of DNA methylation in human placentas. Epigenetics. 2011;6(7):920–927.
22.
FilibertoACMaccaniMAKoestlerD. Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta. Epigenetics. 2011;6(5):566–572.
23.
El HajjNPliushchGSchneiderE. Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus. Diabetes. 2013;62(4):1320–138.
RuchatSMHivertMFBouchardL. Epigenetic programming of obesity and diabetes by in utero exposure to gestational diabetes mellitus. Nutr Rev. 2013;71(suppl 1
):S88–S94.
26.
NomuraYLambertiniLRialdiA. Global methylation in the placenta and umbilical cord blood from pregnancies with maternal gestational diabetes, preeclampsia, and obesity. Reprod Sci. 2014;21(1):131–137.
27.
CarpenterMWCoustanDR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol. 1982;144(7):768–773.
28.
KnablJHuttenbrennerRHutterS. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is down regulated in trophoblast cells of gestational diabetes mellitus (GDM) and in trophoblast tumour cells BeWo in vitro after stimulation with PPARgamma agonists. J Perinat Med. 2014;42(2):179–187.
29.
RemmeleWStegnerHE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987;8(3):138–140.
30.
PavlikRWypiorGHechtS. Induction of G protein-coupled estrogen receptor (GPER) and nuclear steroid hormone receptors by gonadotropins in human granulosa cells. Histochem Cell Biol. 2011;136(3):289–299.
31.
HarderJEngelstaedterVUsadelH. CpG-island methylation of the ER promoter in colorectal cancer: analysis of micrometastases in lymph nodes from UICC stage I and II patients. Br J Cancer. 2009;100(2):360–365.
32.
IssaJPOttavianoYLCelanoPHamiltonSRDavidsonNEBaylinSB. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet. 1994;7(4):536–540.
33.
LapidusRGFergusonATOttavianoYL. Methylation of estrogen and progesterone receptor gene 5’ CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumors. Clin Cancer Res. 1996;2(5):805–810.
34.
EadsCALordRVKurumboorSK. Fields of aberrant CpG island hypermethylation in Barrett’s esophagus and associated adenocarcinoma. Cancer Res. 2000;60(18):5021–5026.
35.
CogswellMEYipR. The influence of fetal and maternal factors on the distribution of birthweight. Semin Perinatol. 1995;19(3):222–240.
36.
AlonsoADel ReyCGNavarroAToliviaJGonzalezCG. Effects of gestational diabetes mellitus on proteins implicated in insulin signaling in human placenta. Gynecol Endocrinol. 2006;22(9):526–535.
37.
KleiblovaPDostalovaIBartlovaM. Expression of adipokines and estrogen receptors in adipose tissue and placenta of patients with gestational diabetes mellitus. Mol Cell Endocrinol. 2010;314(1):150–156.
38.
TothBSaadatGGellerA. Human umbilical vascular endothelial cells express estrogen receptor beta (ERbeta) and progesterone receptor A (PR-A), but not ERalpha and PR-B. Histochem Cell Biol. 2008;130(2):399–405.
39.
BouchardLThibaultSGuaySP. Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy. Diabetes Care. 2010;33(11):2436–2441.
40.
OdaKNishimuraTHiguchiK. Estrogen receptor alpha induction by mitoxantrone increases Abcg2 expression in placental trophoblast cells. J Pharm Sci. 2013;102(9):3364–3372.
41.
GambinoYPMaymoJLPerez-PerezA. 17Beta-estradiol enhances leptin expression in human placental cells through genomic and nongenomic actions. Biol Reprod. 2010;83(1):42–51.
42.
KumarPKamatAMendelsonCR. Estrogen receptor alpha (ERalpha) mediates stimulatory effects of estrogen on aromatase (CYP19) gene expression in human placenta. Mol Endocrinol. 2009;23(6):784–793.
43.
WallaceAEFraserRCartwrightJE. Extravillous trophoblast and decidual natural killer cells: a remodelling partnership. Hum Reprod Update. 2012;18(4):458–471.
44.
WarningJCMcCrackenSAMorrisJM. A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system. Reproduction. 2011;141(6):715–724.
45.
MarchettiBGalloFFarinellaZRomeoCMoraleMC. Luteinizing hormone-releasing hormone (LHRH) receptors in the neuroendocrine-immune network. Biochemical bases and implications for reproductive physiopathology. Ann N Y Acad Sci. 1996;784:209–236.
46.
DebSTessierCPrigent-TessierA. The expression of interleukin-6 (IL-6), IL-6 receptor, and gp130-kilodalton glycoprotein in the rat decidua and a decidual cell line: regulation by 17beta-estradiol and prolactin. Endocrinology. 1999;140(10):4442–4450.
47.
RadaelliTVarastehpourACatalanoPHauguel-de MouzonS. Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes. 2003;52(12):2951–2958.
48.
KnablJHuttenbrennerRHutterS. Gestational diabetes mellitus upregulates vitamin d receptor in extravillous trophoblasts and fetoplacental endothelial cells. Reprod Sci. 2015;22(3):358–366.
49.
AlimirahFPengXYuanL. Crosstalk between the peroxisome proliferator-activated receptor gamma (PPARgamma) and the vitamin D receptor (VDR) in human breast cancer cells: PPARgamma binds to VDR and inhibits 1alpha,25-dihydroxyvitamin D3 mediated transactivation. Exp Cell Res. 2012;318(19):2490–2497.
50.
SchneiderEPliushchGEl HajjN. Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns. Nucleic Acids Res. 2010;38(12):3880–3890.
51.
NilssonMDahlmanIJiaoHGustafssonJAArnerPDahlman-WrightK. Impact of estrogen receptor gene polymorphisms and mRNA levels on obesity and lipolysis--a cohort study. BMC Med Genet. 2007;8:73.
52.
AbotAFontaineCBuscatoM. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;6(10):1328–1346.
53.
Kautzky-WillerAHandisuryaA. Metabolic diseases and associated complications: sex and gender matter!Eur J Clin Invest. 2009;39(8):631–648.
