Evidence from clinical and animal model studies of the long-term and transgenerational impact of stress on DNA methylation.

While it is well-known that stress during development and adulthood can confer long-term neurobiological and behavioral consequences, investigators have only recently begun to assess underlying epigenetic modifications. In this review, we highlight clinical research and work from animal models that provide evidence of the impact of stressful experiences either during the perinatal period or adulthood on DNA methylation and behavior. Additionally, we explore the more controversial concept of transgenerational inheritance, including that associated with preconception stress experienced by the mother or father. Finally, we discuss challenges associated with the idea of transgenerational epigenetics and for the field of epigenetics in general.

[1]  M. Szyf,et al.  Hydroxymethylation and DNA methylation profiles in the prefrontal cortex of the non-human primate rhesus macaque and the impact of maternal deprivation on hydroxymethylation , 2014, Neuroscience.

[2]  J. Buitelaar,et al.  Prenatal stress and risk for psychopathology: specific effects or induction of general susceptibility? , 2004, Psychological bulletin.

[3]  G. Fan,et al.  DNA Methylation and Its Basic Function , 2013, Neuropsychopharmacology.

[4]  T. Elbert,et al.  Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor , 2011, Translational Psychiatry.

[5]  M. Szyf Nongenetic inheritance and transgenerational epigenetics. , 2015, Trends in molecular medicine.

[6]  B. Kolb,et al.  Prenatal bystander stress induces neuroanatomical changes in the prefrontal cortex and hippocampus of developing rat offspring , 2011, Brain Research.

[7]  S. Galea,et al.  SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder , 2011, Depression and anxiety.

[8]  G. Ming,et al.  DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation , 2009, Cell cycle.

[9]  Jill M. Goldstein,et al.  Early Life Programming and Neurodevelopmental Disorders , 2010, Biological Psychiatry.

[10]  A. Weller,et al.  Overweight and CpG methylation of the Pomc promoter in offspring of high‐fat‐diet‐fed dams are not “reprogrammed” by regular chow diet in rats , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  J. Morrison,et al.  Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens , 2010, Nature Neuroscience.

[12]  M. Bakermans-Kranenburg,et al.  Are Children of Holocaust Survivors Less Well-Adapted? A Meta-Analytic Investigation of Secondary Traumatization , 2003, Journal of traumatic stress.

[13]  G. Lynch,et al.  Hippocampal Dysfunction and Cognitive Impairments Provoked by Chronic Early-Life Stress Involve Excessive Activation of CRH Receptors , 2010, The Journal of Neuroscience.

[14]  Michael K. Skinner,et al.  Transgenerational Epigenetic Programming of the Brain Transcriptome and Anxiety Behavior , 2008, PloS one.

[15]  Hein Putter,et al.  DNA methylation signatures link prenatal famine exposure to growth and metabolism , 2014, Nature Communications.

[16]  N. Hiroi,et al.  Neonatal Maternal Separation Alters the Capacity of Adult Neural Precursor Cells to Differentiate into Neurons Via Methylation of Retinoic Acid Receptor Gene Promoter , 2015, Biological Psychiatry.

[17]  M. Leshem,et al.  Prereproductive Stress to Female Rats Alters Corticotropin Releasing Factor Type 1 Expression in Ova and Behavior and Brain Corticotropin Releasing Factor Type 1 Expression in Offspring , 2013, Biological Psychiatry.

[18]  R. Purcell,et al.  Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats , 2014, Epigenetics.

[19]  Ghazala Begum,et al.  Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning , 2012, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  Yi Zhang,et al.  TET enzymes, TDG and the dynamics of DNA demethylation , 2013, Nature.

[21]  Gustavo Turecki,et al.  Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse , 2009, Nature Neuroscience.

[22]  Yi Zhang,et al.  Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation , 2014, Proceedings of the National Academy of Sciences.

[23]  B. Kolb,et al.  Stress during development alters dendritic morphology in the nucleus accumbens and prefrontal cortex , 2012, Neuroscience.

[24]  E. Nestler,et al.  Paternal Transmission of Stress-Induced Pathologies , 2011, Biological Psychiatry.

[25]  C. Kirschbaum,et al.  DNA methylation profiles within the serotonin transporter gene moderate the association of 5-HTTLPR and cortisol stress reactivity , 2014, Translational Psychiatry.

[26]  Michael Papsdorf,et al.  Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses , 2008, Epigenetics.

[27]  Lee E. Edsall,et al.  Human DNA methylomes at base resolution show widespread epigenomic differences , 2009, Nature.

[28]  T. Bale,et al.  Sex-Specific Programming of Offspring Emotionality after Stress Early in Pregnancy , 2008, The Journal of Neuroscience.

[29]  C. Hertzman,et al.  Epigenetic vestiges of early developmental adversity: childhood stress exposure and DNA methylation in adolescence. , 2013, Child development.

[30]  M. Szyf,et al.  DNA Methylation Signatures Triggered by Prenatal Maternal Stress Exposure to a Natural Disaster: Project Ice Storm , 2014, PloS one.

[31]  T. Reyes,et al.  Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. , 2010, Endocrinology.

[32]  S. Beach,et al.  Methylation at 5HTT Mediates the Impact of Child Sex Abuse on Women's Antisocial Behavior: An Examination of the Iowa Adoptee Sample , 2011, Psychosomatic medicine.

[33]  J. Sweatt,et al.  Covalent Modification of DNA Regulates Memory Formation , 2007, Neuron.

[34]  S. Galea,et al.  Epigenetic and immune function profiles associated with posttraumatic stress disorder , 2010, Proceedings of the National Academy of Sciences.

[35]  F. Champagne,et al.  Epigenetic Effects of Prenatal Stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and Fetal Brain , 2012, PloS one.

[36]  S. Matt,et al.  Bdnf DNA methylation modifications in the hippocampus and amygdala of male and female rats exposed to different caregiving environments outside the homecage. , 2014, Developmental psychobiology.

[37]  G. Wolff,et al.  Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. , 2002, The Journal of nutrition.

[38]  Patricia Tueting,et al.  Brain-Derived Neurotrophic Factor Epigenetic Modifications Associated with Schizophrenia-like Phenotype Induced by Prenatal Stress in Mice , 2015, Biological Psychiatry.

[39]  T. Roth,et al.  Differential Methylation of Genes in the Medial Prefrontal Cortex of Developing and Adult Rats Following Exposure to Maltreatment or Nurturing Care During Infancy , 2013, Developmental Neuroscience.

[40]  E. Klein,et al.  DNA methylation in vulnerability to post-traumatic stress in rats: evidence for the role of the post-synaptic density protein Dlgap2. , 2010, The international journal of neuropsychopharmacology.

[41]  T. Bredy,et al.  Methyl CpG Binding Domain Ultra‐Sequencing: a novel method for identifying inter‐individual and cell‐type‐specific variation in DNA methylation , 2014, Genes, brain, and behavior.

[42]  K. Demyttenaere,et al.  Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. , 2013, Journal of psychiatric research.

[43]  D. Phillips,et al.  Transgenerational inheritance of stress pathology , 2012, Experimental Neurology.

[44]  Holger Russig,et al.  Epigenetic Transmission of the Impact of Early Stress Across Generations , 2010, Biological Psychiatry.

[45]  G. Ming,et al.  Neuronal Activity–Induced Gadd45b Promotes Epigenetic DNA Demethylation and Adult Neurogenesis , 2009, Science.

[46]  J. Sweatt,et al.  Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene , 2009, Biological Psychiatry.

[47]  Michael J Meaney,et al.  Genome-wide epigenetic regulation by early-life trauma. , 2012, Archives of general psychiatry.

[48]  W. Aufsatz,et al.  Transgenerational epigenetic inheritance in plants. , 2011, Biochimica et biophysica acta.

[49]  Patrick O. McGowan,et al.  Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus , 2012, Proceedings of the National Academy of Sciences.

[50]  Michael J Meaney,et al.  Epigenetic programming by maternal behavior , 2004, Nature Neuroscience.

[51]  F. Perera,et al.  Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure , 2013, Proceedings of the National Academy of Sciences.

[52]  C. Marsit,et al.  Childhood Adversity and Epigenetic Modulation of the Leukocyte Glucocorticoid Receptor: Preliminary Findings in Healthy Adults , 2012, PloS one.

[53]  T. Roseboom,et al.  Hungry in the womb: what are the consequences? Lessons from the Dutch famine. , 2011, Maturitas.

[54]  T. Roth,et al.  Epigenetic mechanisms in learning and memory. , 2013, Wiley interdisciplinary reviews. Cognitive science.

[55]  Shankar Balasubramanian,et al.  Oxidative bisulfite sequencing of 5-methylcytosine and 5-hydroxymethylcytosine , 2013, Nature Protocols.

[56]  M. Bakermans-Kranenburg,et al.  Does intergenerational transmission of trauma skip a generation? No meta-analytic evidence for tertiary traumatization with third generation of Holocaust survivors , 2008, Attachment & human development.

[57]  A. Guidotti,et al.  Pharmacological Activation of Group-II Metabotropic Glutamate Receptors Corrects a Schizophrenia-Like Phenotype Induced by Prenatal Stress in Mice , 2012, Neuropsychopharmacology.

[58]  C. Kirschbaum,et al.  The 'Trier Social Stress Test'--a tool for investigating psychobiological stress responses in a laboratory setting. , 1993, Neuropsychobiology.

[59]  Yunlong Liu,et al.  Alcohol exposure alters DNA methylation profiles in mouse embryos at early neurulation , 2009, Epigenetics.

[60]  B. Dias,et al.  Parental olfactory experience influences behavior and neural structure in subsequent generations , 2013, Nature Neuroscience.

[61]  K. Braun,et al.  Transgenerational sex-specific impact of preconception stress on the development of dendritic spines and dendritic length in the medial prefrontal cortex , 2014, Brain Structure and Function.

[62]  B. Bradley,et al.  Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions , 2012, Nature Neuroscience.

[63]  D. Diamond,et al.  Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder , 2008, Stress.

[64]  Michael J. Meaney,et al.  Lower Methylation of Glucocorticoid Receptor Gene Promoter 1F in Peripheral Blood of Veterans with Posttraumatic Stress Disorder , 2015, Biological Psychiatry.

[65]  Robert A. Waterland,et al.  Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation , 2003, Molecular and Cellular Biology.

[66]  T. Down,et al.  Germline DNA Demethylation Dynamics and Imprint Erasure Through 5-Hydroxymethylcytosine , 2013, Science.

[67]  M. Szyf,et al.  Adult Glucocorticoid Exposure Leads to Transcriptional and DNA Methylation Changes in Nuclear Steroid Receptors in the Hippocampus and Kidney of Mouse Male Offspring1 , 2014, Biology of reproduction.

[68]  B. Bradley,et al.  Differential immune system DNA methylation and cytokine regulation in post‐traumatic stress disorder , 2011, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[69]  E. Grigorenko,et al.  Differential patterns of whole-genome DNA methylation in institutionalized children and children raised by their biological parents , 2011, Development and Psychopathology.

[70]  B. Bradley,et al.  DNA extracted from saliva for methylation studies of psychiatric traits: Evidence tissue specificity and relatedness to brain , 2015, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[71]  B. Kolb,et al.  Intensity matters: brain, behaviour and the epigenome of prenatally stressed rats , 2011, Neuroscience.

[72]  D. Sarkar,et al.  Male Germline Transmits Fetal Alcohol Adverse Effect on Hypothalamic Proopiomelanocortin Gene Across Generations , 2012, Biological Psychiatry.

[73]  P. Courtet,et al.  Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma , 2011, Translational Psychiatry.

[74]  Stephen T. C. Wong,et al.  MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription , 2008, Science.

[75]  Jennifer A Rusiecki,et al.  DNA methylation in repetitive elements and post-traumatic stress disorder: a case-control study of US military service members. , 2012, Epigenomics.

[76]  S. Guillaume,et al.  Borderline personality disorder and childhood maltreatment: A genome-wide methylation analysis , 2016, European Psychiatry.

[77]  N. Youngson,et al.  Transgenerational epigenetic effects. , 2008, Annual review of genomics and human genetics.

[78]  S. Beach,et al.  Effects of Genotype and Child Abuse on DNA Methylation and Gene Expression at the Serotonin Transporter , 2012, Front. Psychiatry.

[79]  S. Kriaucionis,et al.  DNA modifications: Another stable base in DNA. , 2014, Nature chemistry.

[80]  I. Weaver,et al.  Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. , 2006, Endocrinology.

[81]  J. Flory,et al.  Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. , 2014, The American journal of psychiatry.

[82]  B. Bradley,et al.  Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder , 2013, Proceedings of the National Academy of Sciences.

[83]  E. Koonin,et al.  Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites , 2013, Nucleic acids research.

[84]  E. Jablonka,et al.  'Lamarckian' mechanisms in darwinian evolution. , 1998, Trends in ecology & evolution.

[85]  R. Mychasiuk,et al.  Paternal stress prior to conception alters DNA methylation and behaviour of developing rat offspring , 2013, Neuroscience.

[86]  O. Kovalchuk,et al.  Maternal Stress Induces Epigenetic Signatures of Psychiatric and Neurological Diseases in the Offspring , 2013, PloS one.

[87]  H. Steinbusch,et al.  Differential susceptibility to chronic social defeat stress relates to the number of Dnmt3a-immunoreactive neurons in the hippocampal dentate gyrus , 2015, Psychoneuroendocrinology.

[88]  Christina Thaller,et al.  Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus , 2009, Human molecular genetics.

[89]  J. Sweatt,et al.  Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. , 2011, Journal of psychiatric research.

[90]  Wendy Dean,et al.  Epigenetic reprogramming in early mammalian development and following somatic nuclear transfer. , 2003, Seminars in cell & developmental biology.

[91]  Yonghe Wu,et al.  Early-life stress reduces DNA methylation of the Pomc gene in male mice. , 2014, Endocrinology.

[92]  B. McEwen,et al.  Effects of stress throughout the lifespan on the brain, behaviour and cognition , 2009, Nature Reviews Neuroscience.

[93]  H. Saze Transgenerational inheritance of induced changes in the epigenetic state of chromatin in plants. , 2012, Genes & genetic systems.

[94]  A. Guidotti,et al.  BDNF epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice , 2015 .

[95]  Michael Weber,et al.  Global profiling of DNA methylation erasure in mouse primordial germ cells. , 2012, Genome research.

[96]  David S. Paul,et al.  The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic. , 2012, Toxicology and applied pharmacology.

[97]  A. Guidotti,et al.  Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice , 2013, Neuropharmacology.

[98]  T. Roth,et al.  Exposure to caregiver maltreatment alters expression levels of epigenetic regulators in the medial prefrontal cortex , 2013, International Journal of Developmental Neuroscience.

[99]  J. Sweatt,et al.  Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Fear Memory , 2008, The Journal of Neuroscience.

[100]  Y. Liu,et al.  Maternal Deprivation in Rats is Associated with Corticotrophin‐Releasing Hormone (CRH) Promoter Hypomethylation and Enhances CRH Transcriptional Responses to Stress in Adulthood , 2012, Journal of neuroendocrinology.

[101]  E. Whitelaw,et al.  The case for transgenerational epigenetic inheritance in humans , 2008, Mammalian Genome.

[102]  Patrick O. McGowan,et al.  Broad Epigenetic Signature of Maternal Care in the Brain of Adult Rats , 2011, PloS one.

[103]  Alon Chen,et al.  Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice , 2010, Nature Neuroscience.

[104]  I. Weaver,et al.  Maternal Care Associated with Methylation of the Estrogen Receptor-α1b Promoter and Estrogen Receptor-α Expression in the Medial Preoptic Area of Female Offspring , 2006 .

[105]  M. Skinner,et al.  Epigenetic transgenerational actions of endocrine disruptors. , 2006, Endocrinology.

[106]  F. Holsboer,et al.  Dynamic DNA methylation programs persistent adverse effects of early-life stress , 2009, Nature Neuroscience.

[107]  Zhenli Yu,et al.  Epigenetic Upregulation of Corticotrophin-Releasing Hormone Mediates Postnatal Maternal Separation-Induced Memory Deficiency , 2014, PloS one.

[108]  C. Waddington Canalization of Development and the Inheritance of Acquired Characters , 1942, Nature.

[109]  J. Schulkin,et al.  Transgenerational effects of infantile adversity and enrichment in male and female rats. , 2012, Developmental psychobiology.

[110]  K. Räikkönen,et al.  Epigenomic profiling of men exposed to early-life stress reveals DNA methylation differences in association with current mental state , 2014, Translational Psychiatry.

[111]  A. Puga,et al.  Effects of arsenic exposure on DNA methylation and epigenetic gene regulation. , 2010, Epigenomics.

[112]  D. Patel,et al.  Non-CG methylation patterns shape the epigenetic landscape in Arabidopsis , 2013, Nature Structural & Molecular Biology.

[113]  Takayoshi Suzuki,et al.  Epigenetic Status of Gdnf in the Ventral Striatum Determines Susceptibility and Adaptation to Daily Stressful Events , 2011, Neuron.

[114]  F. Champagne,et al.  Epigenetic perspective on the developmental effects of bisphenol A , 2011, Brain, Behavior, and Immunity.

[115]  M. Szyf,et al.  Differential Glucocorticoid Receptor Exon 1B, 1C, and 1H Expression and Methylation in Suicide Completers with a History of Childhood Abuse , 2012, Biological Psychiatry.

[116]  Eva Jablonka,et al.  Transgenerational Epigenetic Inheritance: Prevalence, Mechanisms, and Implications for the Study of Heredity and Evolution , 2009, The Quarterly Review of Biology.

[117]  A. Baccarelli,et al.  PTSD and DNA Methylation in Select Immune Function Gene Promoter Regions: A Repeated Measures Case-Control Study of U.S. Military Service Members , 2013, Front. Psychiatry.

[118]  D. Hellhammer,et al.  Dynamic changes in DNA methylation of stress-associated genes (OXTR, BDNF ) after acute psychosocial stress , 2012, Translational Psychiatry.