The effects of depression and use of antidepressive medicines during pregnancy on the methylation status of the IGF2 imprinted control regions in the offspring

Clinical Epigenetics

C Hoyo²  MR Forman³  W Demark-Wahnefried¹  J Kurtzberg⁵  F Wang⁶  RL Jirtle⁷  JM Schildkraut²  A Murtha⁴  Z Huang⁴  SK Murphy⁴  A Soubry⁶ 

[1] Dept. of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA;Dept. of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA;Dept. of Epidemiology, M.D. Anderson Cancer Center, Houston, TX, USA;Dept. of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA;Dept. of Pediatrics, Duke University Medical Center, Durham, NC, USA;Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA;Dept. of Radiation Oncology, Duke University Medical Center, Durham, NC, USA

关键词: race;    offspring;    IGF2;    pregnancy;    depression;    antidepressants;   

Others  :  791553
DOI  :  10.1186/1868-7083-3-2

 received in 2011-03-14, accepted in 2011-10-26,  发布年份 2011

【 摘 要 】

In utero exposures to environmental factors may result in persistent epigenetic modifications affecting normal development and susceptibility to chronic diseases in later life. We explored the relationship between exposure of the growing fetus to maternal depression or antidepressants and DNA methylation at two differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene. Aberrant DNA methylation at the IGF2 and neighboring H19 DMRs has been associated with deregulated IGF2 expression, childhood cancers and several chronic diseases during adulthood. Our study population is comprised of pregnant mothers and their newborns (n = 436), as part of the Newborn Epigenetics Study (NEST). A standardized questionnaire was completed and medical record data were abstracted to ascertain maternal depression and antidepressive drug use. DMR methylation levels in umbilical cord blood leukocytes were quantified using pyrosequencing. From the 436 newborns, laboratory data were obtained for 356 individuals at the IGF2 DMRs, and for 411 individuals at the H19 DMRs; about half of each group was African American or Caucasian. While overall no association between depression and methylation profiles was found, we observed a significant hypermethylation of the H19 DMRs in newborns of African American (n = 177) but not Caucasian (n = 168) mothers who reported the use of antidepressive drugs during pregnancy (β = +6.89, p = 0.01). Of note, our data reveal a race-independent association between smoking during pregnancy and methylation at the IGF2 DMR (+3.05%, p = 0.01). In conclusion, our findings suggest a race-dependent response related to maternal use of antidepressants at one of the IGF2 DMRs in the offspring.

【 授权许可】

   
2011 Soubry et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, Lumey LH: Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 2008, 105(44):17046-17049.
• [2]Szyf M, McGowan P, Meaney MJ: The social environment and the epigenome. Environ Mol Mutagen 2008, 49(1):46-60.
• [3]Zhang S, Rattanatray L, Maclaughlin SM, Cropley JE, Suter CM, Molloy L, Kleemann D, Walker SK, Muhlhausler BS, Morrison JL, McMillen IC: Periconceptional undernutrition in normal and overweight ewes leads to increased adrenal growth and epigenetic changes in adrenal IGF2/H19 gene in offspring. FASEB J 2010.
• [4]Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002, 3(6):415-428.
• [5]Jirtle RL, Skinner MK: Environmental epigenomics and disease susceptibility. Nat Rev Genet 2007, 8(4):253-262.
• [6]Waterland RA, Michels KB: Epigenetic epidemiology of the developmental origins hypothesis. Annu Rev Nutr 2007, 27:363-388.
• [7]Evans J, Heron J, Francomb H, Oke S, Golding J: Cohort study of depressed mood during pregnancy and after childbirth. BMJ 2001, 323(7307):257-260.
• [8]Alwan S, Reefhuis J, Rasmussen SA, Friedman JM, Prevention Study TN: Patterns of Antidepressant Medication Use Among Pregnant Women in a United States Population. J Clin Pharmacol 2010.
• [9]Marcus SM, Heringhausen JE: Depression in childbearing women: when depression complicates pregnancy. Prim Care 2009, 36(1):151-165. ix
• [10]Henrichs J, Schenk JJ, Roza SJ, van den Berg MP, Schmidt HG, Steegers EA, Hofman A, Jaddoe VW, Verhulst FC, Tiemeier H: Maternal psychological distress and fetal growth trajectories: the Generation R Study. Psychol Med 2010, 40(4):633-643.
• [11]Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ: A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry 2010, 67(10):1012-1024.
• [12]Oberlander TF, Gingrich JA, Ansorge MS: Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence. Clin Pharmacol Ther 2009, 86(6):672-677.
• [13]Talge NM, Neal C, Glover V: Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? J Child Psychol Psychiatry 2007, 48(3-4):245-261.
• [14]Misri S, Reebye P, Kendrick K, Carter D, Ryan D, Grunau RE, Oberlander TF: Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry 2006, 163(6):1026-1032.
• [15]Pilowsky DJ, Wickramaratne P, Talati A, Tang M, Hughes CW, Garber J, Malloy E, King C, Cerda G, Sood AB, Alpert JE, Trivedi MH, Fava M, Rush AJ, Wisniewski S, Weissman MM: Children of depressed mothers 1 year after the initiation of maternal treatment: findings from the STAR*D-Child Study. Am J Psychiatry 2008, 165(9):1136-1147.
• [16]Wogelius P, Norgaard M, Gislum M, Pedersen L, Munk E, Mortensen PB, Lipworth L, Sorensen HT: Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology 2006, 17(6):701-704.
• [17]Cole JA, Ephross SA, Cosmatos IS, Walker AM: Paroxetine in the first trimester and the prevalence of congenital malformations. Pharmacoepidemiol Drug Saf 2007, 16(10):1075-1085.
• [18]Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM: Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007, 356(26):2684-2692.
• [19]Oberlander TF, Warburton W, Misri S, Riggs W, Aghajanian J, Hertzman C: Major congenital malformations following prenatal exposure to serotonin reuptake inhibitors and benzodiazepines using population-based health data. Birth Defects Res B Dev Reprod Toxicol 2008, 83(1):68-76.
• [20]Berard A, Ramos E, Rey E, Blais L, St-Andre M, Oraichi D: First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol 2007, 80(1):18-27.
• [21]Swanson JM, Entringer S, Buss C, Wadhwa PD: Developmental origins of health and disease: environmental exposures. Semin Reprod Med 2009, 27(5):391-402.
• [22]Marsella M, Ubaldini E, Solinas A, Guerrini P: Prenatal exposure to serotonin reuptake inhibitors: a case report. Ital J Pediatr 2010, 36(1):27. BioMed Central Full Text
• [23]McGowan PO, Kato T: Epigenetics in mood disorders. Environ Health Prev Med 2008, 13(1):16-24.
• [24]Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ: Epigenetic programming by maternal behavior. Nat Neurosci 2004, 7(8):847-854.
• [25]Miller CA, Sweatt JD: Covalent modification of DNA regulates memory formation. Neuron 2007, 53(6):857-869.
• [26]McGowan PO, Sasaki A, Huang TC, Unterberger A, Suderman M, Ernst C, Meaney MJ, Turecki G, Szyf M: Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS One 2008, 3(5):e2085.
• [27]McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonte B, Szyf M, Turecki G, Meaney MJ: Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009, 12(3):342-348.
• [28]Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM: Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 2008, 3(2):97-106.
• [29]Ulaner GA, Vu TH, Li T, Hu JF, Yao XM, Yang Y, Gorlick R, Meyers P, Healey J, Ladanyi M, Hoffman AR: Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site. Hum Mol Genet 2003, 12(5):535-549.
• [30]Bell AC, Felsenfeld G: Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 2000, 405(6785):482-485.
• [31]Murrell A, Ito Y, Verde G, Huddleston J, Woodfine K, Silengo MC, Spreafico F, Perotti D, De Crescenzo A, Sparago A, Cerrato F, Riccio A: Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer. PLoS One 2008, 3(3):e1849.
• [32]Hoyo C, Murphy SK, Jirtle RL: Imprint regulatory elements as epigenetic biosensors of exposure in epidemiological studies. J Epidemiol Community Health 2009, 63(9):683-684.
• [33]Heijmans BT, Tobi EW, Lumey LH, Slagboom PE: The epigenome: archive of the prenatal environment. Epigenetics 2009, 4(8):526-531.
• [34]Hoyo C, Murtha AP, Schildkraut JM, Forman MR, Calingaert B, Demark-Wahnefried W, Kurtzberg J, Jirtle RL, Murphy SK: Folic acid supplementation before and during pregnancy in the Newborn Epigenetics STudy (NEST). BMC Public Health 2011, 11(1):46. BioMed Central Full Text
• [35]Cui H, Onyango P, Brandenburg S, Wu Y, Hsieh CL, Feinberg AP: Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res 2002, 62(22):6442-6446.
• [36]Cui H, Niemitz EL, Ravenel JD, Onyango P, Brandenburg SA, Lobanenkov VV, Feinberg AP: Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Res 2001, 61(13):4947-4950.
• [37]Hoyo C, Murtha AP, Schildkraut JM, Jirtle RL, Demark-Wahnefried W, Forman MR, Iversen ES, Kurtzberg J, Overcash F, Huang Z, Murphy SK: Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy. Epigenetics 2011., 6(7)
• [38]Maldonado G, Greenland S: Simulation study of confounder-selection strategies. Am J Epidemiol 1993, 138(11):923-936.
• [39]Cooper WO, Willy ME, Pont SJ, Ray WA: Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007, 196(6):544. e541-545
• [40]Kim J, Riggs KW, Misri S, Kent N, Oberlander TF, Grunau RE, Fitzgerald C, Rurak DW: Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding. Br J Clin Pharmacol 2006, 61(2):155-163.
• [41]Oberlander TF, Warburton W, Misri S, Aghajanian J, Hertzman C: Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and materna l depression using population-based linked health data. Arch Gen Psychiatry 2006, 63(8):898-906.
• [42]Lattimore KA, Donn SM, Kaciroti N, Kemper AR, Neal CR, Vazquez DM: Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and effects on the fetus and newborn: a meta-analysis. J Perinatol 2005, 25(9):595-604.
• [43]Zhu SH, Valbo A: Depression and smoking during pregnancy. Addict Behav 2002, 27(4):649-658.
• [44]Linares Scott TJ, Heil SH, Higgins ST, Badger GJ, Bernstein IM: Depressive symptoms predict smoking status among pregnant women. Addict Behav 2009, 34(8):705-708.
• [45]Yau JL, Noble J, Chapman KE, Seckl JR: Differential regulation of variant glucocorticoid receptor mRNAs in the rat hippocampus by the antidepressant fluoxetine. Brain Res Mol Brain Res 2004, 129(1-2):189-192.
• [46]Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Danton F, Thibaud N, Le Merrer M, Burglen L, Bertrand AM, Netchine I, Le Bouc Y: Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 2005, 37(9):1003-1007.
• [47]Eggermann T, Eggermann K, Schonherr N: Growth retardation versus overgrowth: Silver-Russell syndrome is genetically opposite to Beckwith-Wiedemann syndrome. Trends Genet 2008, 24(4):195-204.
• [48]Murphy SK, Huang Z, Wen Y, Spillman MA, Whitaker RS, Simel LR, Nichols TD, Marks JR, Berchuck A: Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer. Mol Cancer Res 2006, 4(4):283-292.
• [49]Steenman MJ, Rainier S, Dobry CJ, Grundy P, Horon IL, Feinberg AP: Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. Nat Genet 1994, 7(3):433-439.
• [50]Kramer S, Meadows AT, Jarrett P: Racial variation in incidence of Wilms' tumor: relationship to congenital anomalies. Med Pediatr Oncol 1984, 12(6):401-405.
• [51]Woodson K, Gillespie J, Hanson J, Emmert-Buck M, Phillips JM, Linehan WM, Tangrea JA: Heterogeneous gene methylation patterns among pre-invasive and cancerous lesions of the prostate: a histopathologic study of whole mount prostate specimens. Prostate 2004, 60(1):25-31.
• [52]Woodson K, Hanson J, Tangrea J: A survey of gene-specific methylation in human prostate cancer among black and white men. Cancer Lett 2004, 205(2):181-188.
• [53]Woodson K, Hayes R, Wideroff L, Villaruz L, Tangrea J: Hypermethylation of GSTP1, CD44, and E-cadherin genes in prostate cancer among US Blacks and Whites. Prostate 2003, 55(3):199-205.
• [54]Powell MA, Mutch DG, Rader JS, Herzog TJ, Huang TH, Goodfellow PJ: Ribosomal DNA methylation in patients with endometrial carcinoma: an independent prognostic marker. Cancer 2002, 94(11):2941-2952.
• [55]Haiman CA, Stram DO: Exploring genetic susceptibility to cancer in diverse populations. Curr Opin Genet Dev 2010.
• [56]US BC: 2005-2009 American Community Survey 5-Year Estimates; Durham County, NC; S1301. In Fertility. Washington, DC; 2010.
• [57]CDC: Trends in smoking before, during, and after pregnancy -- pregnancy risk assessment monitoring system (prams), united states, 31 sites, 2000-2005. Surveillance Summaries 2009, SS-4.
• [58]Harman JS, Edlund MJ, Fortney JC: Trends in antidepressant utilization from 2001 to 2004. Psychiatr Serv 2009, 60(5):611-616.