Ancestral exposure to stress epigenetically programs preterm birth risk and adverse maternal and newborn outcomes

BMC Medicine

Gerlinde AS Metz³  David M Olson²  Igor Kovalchuk¹  Olga Kovalchuk¹  Olena Babenko¹  Jerrah C Robbins³  Fabiola CR Zucchi³  Alexandra M Robinson³  Youli Yao¹ 

[1] Department of Biological Sciences, University of Lethbridge, 4401 University Drive, Lethbridge T1K3M4, AB, Canada;Departments of Obstetrics & Gynecology, Pediatrics and Physiology, University of Alberta, 227 HMRC, Edmonton T6G2S2, AB, Canada;Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge T1K3M4, AB, Canada

关键词: pregnancy;    perinatal programming;    behavioural development;    maternal health;    gestation;    epigenetic regulation;    microRNA;    transgenerational inheritance;    prenatal stress;    maternal stress;    Preterm birth;   

Others  :  1121564
DOI  :  10.1186/s12916-014-0121-6

 received in 2014-01-10, accepted in 2014-07-01,  发布年份 2014

【 摘 要 】

Background

Chronic stress is considered to be one of many causes of human preterm birth (PTB), but no direct evidence has yet been provided. Here we show in rats that stress across generations has downstream effects on endocrine, metabolic and behavioural manifestations of PTB possibly via microRNA (miRNA) regulation.

Methods

Pregnant dams of the parental generation were exposed to stress from gestational days 12 to 18. Their pregnant daughters (F1) and grand-daughters (F2) either were stressed or remained as non-stressed controls. Gestational length, maternal gestational weight gain, blood glucose and plasma corticosterone levels, litter size and offspring weight gain from postnatal days 1 to 30 were recorded in each generation, including F3. Maternal behaviours were analysed for the first hour after completed parturition, and offspring sensorimotor development was recorded on postnatal day (P) 7. F0 through F2 maternal brain frontal cortex, uterus and placenta miRNA and gene expression patterns were used to identify stress-induced epigenetic regulatory pathways of maternal behaviour and pregnancy maintenance.

Results

Progressively up to the F2 generation, stress gradually reduced gestational length, maternal weight gain and behavioural activity, and increased blood glucose levels. Reduced offspring growth and delayed behavioural development in the stress cohort was recognizable as early as P7, with the greatest effect in the F3 offspring of transgenerationally stressed mothers. Furthermore, stress altered miRNA expression patterns in the brain and uterus of F2 mothers, including the miR-200 family, which regulates pathways related to brain plasticity and parturition, respectively. Main miR-200 family target genes in the uterus, Stat5b, Zeb1 and Zeb2, were downregulated by multigenerational stress in the F1 generation. Zeb2 was also reduced in the stressed F2 generation, suggesting a causal mechanism for disturbed pregnancy maintenance. Additionally, stress increased placental miR-181a, a marker of human PTB.

Conclusions

The findings indicate that a family history of stress may program central and peripheral pathways regulating gestational length and maternal and newborn health outcomes in the maternal lineage. This new paradigm may model the origin of many human PTB causes.

【 授权许可】

   
2014 Yao et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Mikkola K, Ritari N, Tommiska V, Salokorpi T, Lehtonen L, Tammela O, Pääkkönen L, Olsen P, Korkman M, Fellman V: Neurodevelopmental outcome at 5 years of age of a national cohort of extremely low birth weight infants who were born in 1996-1997. Pediatrics 2005, 116:1391-1400.
• [2]Kramer MS, Lydon J, Goulet L, Kahn S, Dahhou M, Platt RW, Sharma S, Meaney MJ, Séguin L: Maternal stress/distress, hormonal pathways and spontaneous preterm birth. Paediatr Perinat Epidemiol 2013, 27:237-246.
• [3]Hobel CJ: Stress and preterm birth. Clin Obstet Gyn 2004, 47:856-880.
• [4]Zhu P, Tao F, Hao J, Sun Y, Jiang X: Prenatal life events stress: implications for preterm birth and infant birthweight. Am J Obstet Gynecol 2010, 203:34.e1-8.
• [5]Emanuel I, Leisenring W, Wiliams MA, Kimpo C, Estee S, O’Brien W, Hale CB: The Washington state intergenerational study of birth outcomes: methodology and some comparisons of maternal birth weight and infant birthweight and gestation in four ethnic groups. Paediatr Perinat Epidemiol 1999, 13:352-371.
• [6]Rich-Edwards JW, Grizzard TA: Psychosocial stress and neuroendocrine mechanisms in preterm delivery. Am J Obstet Gynecol 2005, 192:S30-S35.
• [7]Wainstock T, Anteby E, Glasser S, Shoham-Vardi I, Lerner-Geva L: The association between prenatal maternal objective stress, perceived stress, preterm birth and low birthweight. J Matern Fetal Neonatal Med 2013, 26:973-977.
• [8]Porter F, Fraser AM, Hunter CY, Ward H, Varner MW: The risk of preterm birth across generations. Obstet Gynecol 1997, 90:63-67.
• [9]Crews D, Gillette R, Scarpino SV, Manikkam M, Savenkova MI, Skinner MK: Epigenetic transgenerational inheritance of altered stress responses. Proc Natl Acad Sci U S A 2012, 109:9143-9148.
• [10]Morgan CP, Bale TL: Early prenatal stress epigenetically programs dysmasculinization in second-generation offspring via the paternal lineage. J Neurosci 2011, 31:11748-11755.
• [11]Dias BG, Ressler KJ: Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci 2014, 17:89-96.
• [12]Gapp K, Jawaid A, Sarkies P, Bohacek J, Pelczar P, Prados J, Farinelli L, Miska E, Mansuy IM: Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 2014, 17:667-669.
• [13]Nilsson EE, Anway MD, Stanfield J, Skinner MK: Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease. Reproduction 2008, 135:713-721.
• [14]Skinner MK, Manikkam M, Tracey R, Guerrero-Bosagna C, Haque M, Nilsson EE: Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity. BMC Med 2013, 11:228. BioMed Central Full Text
• [15]Veenendaal MV, Painter RC, de Rooij SR, Bossuyt PM, van der Post JA, Gluckman PD, Hanson MA, Roseboom TJ: Transgenerational effects of prenatal exposure to the 1944-45 Dutch famine. BJOG 2013, 120:548-553.
• [16]Skinner MK: What is an epigenetic transgenerational phenotype? F3 or F2. Reprod Toxicol 2008, 25:2-6.
• [17]Skinner MK, Manikkam M, Guerrero-Bosagna C: Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab 2010, 21:214-222.
• [18]Renthal NE, Chen CC, Williams KC, Gerard RD, Prange-Kiel J, Mendelson CR: miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. Proc Natl Acad Sci U S A 2010, 107:20828-20833.
• [19]Williams KC, Renthal NE, Condon JC, Gerard RD, Mendelson CR: MicroRNA-200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor. Proc Natl Acad Sci U S A 2012, 109:7529-7534.
• [20]Metz GA, Jadavji NM, Smith LK: Modulation of motor function by stress: a novel concept of the effects of stress and corticosterone on behavior. Eur J Neurosci 2005, 22:1190-1200.
• [21]Ward ID, Zucchi FCR, Robbins J, Falkenberg EA, Olson DM, Benzies K, Metz GA: Transgenerational programming of maternal behaviour by prenatal stress. BMC Pregnancy Childbirth 2013, 13:S9. BioMed Central Full Text
• [22]Zucchi FC, Yao Y, Ward ID, Ilnytskyy Y, Olson DM, Benzies K, Kovalchuk I, Kovalchuk O, Metz GA: Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring. PLoS One 2013, 8:e56967.
• [23]Ellenbroek BA, Derks N, Park HJ: Early maternal deprivation retards neurodevelopment in Wistar rats. Stress 2005, 8:247-257.
• [24]Gao X, Gulari E, Zhou X: In situ synthesis of oligonucleotide microarrays. Biopolymers 2004, 73:579-596.
• [25]Zhu Q, Hong A, Sheng N, Zhang X, Jun KY, Srivannavit O, Gulari E, Gao X, Zhou X: Microfluidic biochip for nucleic acid and protein analysis. Methods Mol Biol 2007, 382:287-312.
• [26]Bolstad BM, Irizarry RA, Astrandand M, Speed TP: A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 2003, 19:185-193.
• [27]Wan G, Lim QE, Too HP: High-performance quantification of mature microRNAs by real-time RT-PCR using deoxyuridine-incorporated oligonucleotides and hemi-nested primers. RNA 2010, 16:1436-1445.
• [28]Eisen MB, Spellman PT, Brown PO, Botstein D: Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 1998, 95:14863-14868.
• [29]Betel D, Koppal A, Agius P, Sander C, Leslie C: Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. [http://www.microrna.org/] webciteGenome Biol 2010, 11:R90. http://www.microrna.org/ BioMed Central Full Text
• [30]Huang DW, Sherman BT, Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources. [http://david.abcc.ncifcrf.gov/] webciteNature Protoc 2009, 4:44-57. http://david.abcc.ncifcrf.gov/
• [31]Mi H, Lazareva-Ulitsky B, Loo R, Kejariwal A, Vandergriff J, Rabkin S, Guo N, Muruganujan A, Doremieux O, Campbell MJ, Kitano H, Thomas PD: The PANTHER database of protein families, subfamilies, functions and pathways. [http://www.pantherdb.org/] webciteNucl Acids Res 2005, 33:D284-D288. http://www.pantherdb.org/
• [32]Mayor-Lynn K, Toloubeydokhti T, Cruz AC, Chegini N: Expression profile of microRNAs and mRNAs in human placentas from pregnancies complicated by preeclampsia and preterm labor. Reprod Sci 2011, 18:46-56.
• [33]Cottrell EC, Seckl JR: Prenatal stress, glucocorticoids and the programming of adult disease. Front Behav Neurosci 2009, 3:1-9.
• [34]Schwab M: Intrauterine programming of disorders of brain function in later life. Gynakol Geburtshilfliche Rundsch 2009, 49:13-28. [in German]
• [35]Räikkönen K, Pesonen AK, Roseboom TJ, Eriksson JG: Early determinants of mental health. Best Pract Res Clin Endocrinol Metab 2012, 26:599-611.
• [36]Miller AE, Riegle GD: Progesterone and luteinizing hormone secretion following stress-induced interruption of constant estrus in aged rats. J Gerontol 1985, 40:129-132.
• [37]Arck PC: Stress and pregnancy loss: role of immune mediators, hormones and neurotransmitters. Am J Reprod Immunol 2001, 46:117-123.
• [38]Berends LM, Ozanne SE: Early determinants of type-2 diabetes. Best Pract Res Clin Endocrinol Metab 2012, 26:569-580.
• [39]Glynn LM, Wadhwa PD, Dunkel-Schetter C, Chicz-DeMet A, Sandman CA: When stress happens matters: effects of earthquake timing on stress responsivity in pregnancy. Obstetrics 2000, 184:637-642.
• [40]Van den Hove DL, Blanco CE, Scheepens A, Desbonnet L, Myint AM, Leonard BE, Prickaerts J, Steinbusch HW: Prenatal maternal paroxetine treatment and neonatal mortality in the rat: a preliminary study. Neonatology 2008, 93:52-55.
• [41]Olivier JD, Akerud H, Kaihola H, Pawluski JL, Skalkidou A, Högberg U, Sundström-Poromaa I: The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on offspring. Front Cell Neurosci 2013, 7:73.
• [42]Xu Z, Zhao J, Zhang H, Ke T, Xu P, Cai W, Katirai F, Ye D, Huang Y, Huang B: Spontaneous miscarriages are explained by the stress/glucocorticoid/lipoxin A4 axis. J Immuno 2013, 190:6051-6058.
• [43]Cheek TG, Baird E: Anesthesia for nonobstetric surgery: maternal and fetal considerations. Clin Obstet Gynecol 2009, 52:535-545.
• [44]Uchida S, Hara K, Kobayashi A, Otsuki K, Hobara T, Yamagata H, Watanabe Y: Maternal and genetic factors in stress-resilient and -vulnerable rats: a cross-fostering study. Brain Res 2010, 1316:43-50.
• [45]Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ, Szyf M: Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci 2005, 25:11045-11054.
• [46]Zhang TY, Hellstrom IC, Bagot RC, Wen X, Diorio J, Meaney MJ: Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus. J Neurosci 2010, 30:13130-13137.
• [47]Champagne FA, Meaney MJ: Transgenerational effects of social environment on variations in maternal care and behavioral response to novelty. Behav Neurosci 2007, 121:1353-1363.
• [48]Babenko O, Golubov A, Ilnytskyy Y, Kovalchuk I, Metz GA: Genomic and epigenomic responses to chronic stress involve miRNA-mediated programming. PLoS One 2012, 7:e29441.
• [49]Lin ST, Fu YH: miR-23 regulation of lamin B1 is crucial for oligodendrocyte development and myelination. Dis Model Mech 2009, 2:178-188.
• [50]Jin J, Cheng Y, Zhang Y, Wood W, Peng Q, Hutchison E, Mattson MP, Becker KG, Duan W: Interrogation of brain miRNA and mRNA expression profiles reveals a molecular regulatory network that is perturbed by mutant huntingtin. J Neurochem 2012, 123:477-490.
• [51]Wagner KV, Hartmann J, Mangold K, Wang XD, Labermaier C, Liebl C, Wolf M, Gassen NC, Holsboer F, Rein T, Müller MB, Schmidt MV: Homer1 mediates acute stress-induced cognitive deficits in the dorsal hippocampus. J Neurosci 2013, 33:3857-3864.
• [52]Griggs EM, Young EJ, Rumbaugh G, Miller CA: MicroRNA-182 regulates amygdala-dependent memory formation. J Neurosci 2013, 33:1734-1740.
• [53]Wu Y, Xiao Y, Ding X, Zhuo Y, Ren P, Zhou C, Zhou J: A miR-200b/200c/429-binding site polymorphism in the 3′ untranslated region of the AP-2α gene is associated with cisplatin resistance. PLoS One 2011, 6:e29043.
• [54]Haramati S, Navon I, Issler O, Ezra-Nevo G, Gil S, Zwang R, Hornstein E, Chen A: microRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34. J Neurosci 2011, 31:14191-14203.
• [55]Babenko O, Kovalchuk I, Metz GA: Environmental influences on epigenetic programming of neurodegenerative diseases. Brain Res 2012, 1444:96-111.
• [56]Christiaens I, Zaragoza DB, Guilbert L, Robertson SA, Mitchell BF, Olson DM: Inflammatory processes in preterm and term parturition. J Reprod Immunol 2008, 79:50-57.
• [57]Kossintseva I, Wong S, Johnstone E, Guilbert L, Olson DM, Mitchell BF: Proinflammatory cytokines inhibit human placental 11beta-hydroxysteroid dehydrogenase type 2 activity through Ca2+ and cAMP pathways. Am J Physiol Endocrinol Metab 2006, 290:E282-E288.
• [58]Nothnick WB, Healy C: Estrogen induces distinct patterns of microRNA expression within the mouse uterus. Reprod Sci 2010, 17:987-994.
• [59]Hou L, Lu Y, Li Y, Li L: MicroRNA-451 (miRNA-451) is a potential biomarker for estrogenicity in mouse uterus. Front Envir Sci Engineer 2014, 1:99-105.
• [60]Heard E, Martienssen RA: Transgenerational epigeneticinheritance: myths and mechanisms. Cell 2014, 157:95-109.
• [61]Migikovsky Z, Kovalchuk I: Epigenetic memory in mammals. Front Genet 2011, 2:28.
• [62]Zucchi FC, Yao Y, Metz GA: The secret language of destiny: stress imprinting and transgenerational origins of disease. Front Genet 2012, 3:96.