- Email: [email protected]
Epigenetic perpetuation of the impact of early life stress on behavior
Available online at www.sciencedirect.com
ScienceDirect Epigenetic perpetuation of the impact of early life stress on behavior Linda Witek Janusek1, Dina Tell1 and Herbert L Mathews2 There is growing support for epigenetic perpetuation of early life stressful experiences on offspring behavior. Evidence primarily exists for maternal psychosocial experiences (i.e. mood and exposure to stress, adversity, or trauma) to associate with epigenetic modification to offspring genes involved in neurobehavioral pathways (i.e. glucocorticoid, oxytocin, and serotonin system genes). Such epigenetic modifications associate with altered infant neurobehavioral developmental profiles, stress reactivity, and maladaptive behaviors observed in childhood and/or adolescence. Epigenetic transmission of adverse early life experiences to the offspring genome most often occurs during the prenatal and early postnatal periods, when developing systems are more sensitive to environmental signals. Emerging work suggests interventions that foster positive maternal–infant interactions may attenuate the epigenetic impact of early life stress. Addresses 1 Marcella Niehoff School of Nursing, Department of Health Promotion, Loyola University Chicago, Health Science Division, 2160 South First Ave., Maywood, IL 60153, United States 2 Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Health Science Division, 2160 South First Ave., Maywood, IL 60153, United States Corresponding author: Janusek, Linda Witek ([email protected])
Current Opinion in Behavioral Sciences 2019, 28C:1–7 This review comes from a themed issue on Psychoneuroimmunology Edited by Suzanne Segerstrom and Deborah Hodgson
https://doi.org/10.1016/j.cobeha.2019.01.004 2352-1546/ã 2018 Elsevier Ltd. All rights reserved.
structure to affect gene expression independent of a change in DNA sequence. Although DNA encodes for genes using a sequence of nucleotide bases (adenine, thymine, guanine, and cytosine), epigenetic modifications influence the level of gene expression, either amplifying or diminishing expression. A unifying epigenetic concept is phenotypic plasticity, wherein a cell’s epigenetic signature (i.e. epigenome) is modifiable by the environment. Thus, an epigenetic signature provides a layer of variation that may mediate the relationship between genotype and environmental exposure. Epigenetic modifications can be passed across generations of both somatic and germline cells, allowing durable (and potentially cross-generational) influences. For a recent review, see Ref. [1]. Since epigenetic processes are sensitive to the environment, including the psychosocial environment, epigenetics provides a framework to understand the biological mechanisms, by which early life environmental signals influence future behavior. The discovery that epigenetic processes translate the early psychosocial environment to the genome is one of the most intriguing lines of investigation in contemporary biology. This review will focus on recent investigations in humans, which examine epigenetic processes as a mechanism, by which early life experiences influence offspring behavior. Most of such investigations have focused on the consequence of maternal prenatal experiences (i.e. maternal mood, and exposure to stress, trauma, or social adversity) and/or the impact of an adverse early postnatal environment [2]. Although paternal influences on offspring behavioral development may occur through epigenetic modification, either to sperm DNA or through fathers’ caregiving, such research is limited. Figure 2 describes the framework guiding this review.
Early life stress and stress-related genes Introduction The early life psychosocial environment is a powerful determinant of development. An adverse intrauterine environment, as well as a non-nurturing postnatal environment, can exert enduring biological effects that shape future behavior. A key question is what biological process perpetuates the impact of these early experiences on future behavior? One process by which this may occur is through epigenetic modification of the offspring genome. Epigenetic modification refers to a variety of processes, illustrated in Figure 1 that modify chromatin www.sciencedirect.com
Early life stress may influence offspring behavior through epigenetic processes that affect developing stress response systems, particularly the hypothalamic– pituitary–adrenal (HPA) axis. Stress activation of the HPA axis results in the release of cortisol, the body’s main glucocorticoid (GC). Cortisol plays a key role in fetal brain development, and accordingly, negative feedback mechanisms tightly regulate cortisol levels. Excessive exposure to cortisol, due to epigenetic alterations of GC-related genes, is linked to poor neurobehavioral outcomes [3]. Of GC-related genes, the GC receptor (GR) (Nuclear Receptor Subfamily 3 Group C Member 1, Current Opinion in Behavioral Sciences 2019, 28:1–7
2 Psychoneuroimmunology
Figure 1
DNA methylation
Genes
DNase I hypersensitive sites
Chromatin
RNA
Histone Modifications
Current Opinion in Behavioral Sciences
Key epigenetic processes that influence gene expression. Epigenetics refers to heritable phenotypic changes in gene expression that do not involve alterations in the sequence of DNA. Several epigenetic processes regulate gene expression and genome activity. DNA methylation is the most extensively studied. DNA methylation attaches a methyl group to DNA, primarily at a cytosine base adjacent to a guanine residue, producing 5-methylcytosine (other chemical modifications of cytosine bases in DNA have also been described). In broad terms the presence of 5methylcytosine often represses DNA transcription. Another epigenetic process regulating gene expression and genome activity is histone modification. DNA is wrapped around histone proteins creating nucleosomes that can be chemically modified to alter gene expression. A number of histone post-translational modifications (e.g. lysine acetylation) can change chromatin structure or recruit transcriptional cofactors to DNA that increase gene expression. Alternatively, modifications (e.g. lysine methylation) can act to repress or reduce gene expression (e.g. in heterochromatin). Non-coding RNA molecules can also act epigenetically. These are small or long RNA molecules that do not code for a protein, but rather function to regulate gene expression. These non-coding RNA molecules are not DNA sequence-dependent, so the majority do not rely on a nucleotide sequence that is complimentary to a specific DNA or RNA region in order to function. Non-coding RNAs are examples of RNA classes that are present in sperm and can act epigenetically to affect subsequent generations. For a recent review see Ref. [1]. Illustration from the National Institutes of Health Roadmap Epigenomics http://www.roadmapepigenomics.org/.
NR3C1), has been the most explored. Although several different NR3C1 regions have been investigated, exon 1F of NR3C1 has been consistently shown to be epigenetically influenced by stress. Exon 1F contains a DNA sequence element that encodes a methylation-sensitive binding site for the neural activity-regulated transcription activator, NGF1A/EGR1. Reduced transcription of NR3C1 due to increased methylation of this binding site diminishes GC-GR mediated negative feedback within the hypothalamus. As a result, inappropriate elevations of cortisol can impair development of offspring neurobehavioral pathways. For example, meta-analysis of mothers (977 subjects across seven studies) who reported anxiousdepressive behavior or exposure to violence during pregnancy demonstrated correlations among increased offspring DNA methylation and prenatal stress at CpG positon 36 of NR3C1 1F [4]. Adjacent positions 35, 37, 38, or 39 and other positions did not correlate with maternal stress. It is important to note that differences in DNA methylation technologies or individual differences in the psychosocial circumstances may account for the lack of correlations among these and other CpG residues across investigations. Although results are Current Opinion in Behavioral Sciences 2019, 28:1–7
mixed, there is a growing support for a connection among NR3C1 methylation, early life experiences, and behavior in humans.
Early life stress and epigenetic modification of placental GC-related genes The placenta regulates the intrauterine environment, protecting the fetus from environmental insults. Stress exposure may induce epigenetic alterations of placental GC-related genes, HSD11B2 and NR3C1. Both genes are highly expressed in the placenta and associate with perinatal stress. HSD11B2 encodes the enzyme, 11-beta hydroxysteroid dehydrogenase type 2, which inactivates cortisol, thereby shielding the fetus from the damaging effects of excess cortisol. However, the capacity for HSD11B2 to buffer excess cortisol is limited, allowing maternal stress to expose the fetus to excess cortisol [5]. Two categories of investigations link epigenetic modification of placental NR3C1 and HSD11B2 to poor neurobehavioral outcomes: (1) those demonstrating relationships between epigenetic modification of placental genes and infant neurodevelopment; and (2) those suggesting placental epigenetic mechanisms mediate the effect of www.sciencedirect.com
Epigenetics, early life stress, and behavior Janusek, Tell and Mathews 3
Figure 2 Life stress, adversity, trauma
Preconception
Intrauterine
Infancy
Childhood/ adolescence
Epigenetic processes
Behavioral phenotype Current Opinion in Behavioral Sciences
Epigenetic perpetuation of the impact of early life stress, adversity and trauma on behavioral phenotype. Epigenetic processes provide a framework for understanding the biological mechanisms by which pre-natal and post-natal environmental events influence offspring behavior. Epigenetic modifications, such as DNA methylation, can be passed on during cell division and confer long-term phenotypic changes. Epigenetic processes are sensitive to the environment. As a result, environmental stress, adversity, or trauma can trigger epigenetic modification across the developmental spectrum, from parental exposures that affect germ cells (pre-conception) to offspring exposures stemming from the intrauterine and/or early postnatal environment. During development, there are critical biological windows in which environmental influences are more likely to alter epigenetic processes and influence behavioral phenotype. Behavioral epigenetics is a field of study that investigates antecedents (e.g. stress, adversity, and trauma) and outcomes of epigenetic modifications in genes (e.g. stress-related genes) involved in the development of behavior.
prenatal factors on infant neurodevelopment [6]. Common infant neurobehaviors associated with differential methylation of placental NR3C1 are attention and quality of movement [7]. Moreover, interactions between placental NR3C1 and HSD11B2 methylation associate with distinct domains of infant neurobehavioral phenotypes [8]. For example, methylation of NR3C1 associates with a reactive, poorly regulated behavioral profile; while methylation of HSD11B2 reduces risk for this behavior [9]. A critical question is whether epigenetic changes to GCrelated genes associate not only with infant neurobehavior, but also with infant stress reactivity. This was demonstrated when greater methylation of placental NR3C1 was shown to predict greater infant cortisol stress reactivity, as well as infant self-regulation at five months of age [10]. Both a robust HPA stress response and infant ability to self-regulate (i.e. organize behavior) in response to stress are critical developmental milestones that forecast future psychological health [11]. Beyond methylation analysis, other epigenetic processes may be operative, but not as well investigated. For example, decreased expression of microRNAs (miRNAs) has been associated with infant attention and quality of movement. Specifically, miRNAs from term placentas exhibited increased miR-16 expression that negatively associated with reduced attention, while increased miR14a and increased miR-182 associated with better quality of movement [12]. These miRNAs target multiple genes, www.sciencedirect.com
including the serotonin receptor. Using an epigenomewide approach, variable methylation in 50 placental genes associated with infant neurobehavior (attention, lethargy, quality of movement, and arousal) has been reported. Gene ontology analysis supports a role for these genes in brain development [13].
Maternal social adversity and mood Social adversity may influence pregnancy outcomes through epigenetic processes, exerting effects before pregnancy, during pregnancy, or throughout the early caregiving years [14] [15]. For instance, infants of mothers experiencing socioeconomic adversity during pregnancy exhibited decreased placental HSD11B2 methylation, most evident in males [16]. Reduced methylation of placental HSD11B2 theoretically increases transcription of this enzyme, enhancing fetal capacity to inactivate excess maternal cortisol resulting from socioeconomic stress. Possibly, the chronicity of socioeconomic stress may foster an ‘adaptive epigenetic profile,’ which differs from that resulting from acute or traumatic stressors. Emerging work suggests epigenetic processes resulting from adverse early life adverse social conditions contribute to altered stress reactivity, and risk for health disparity [17]. An important line of investigation is whether maternal mood engenders epigenetic modification of offspring genes. A seminal study demonstrated maternal Current Opinion in Behavioral Sciences 2019, 28:1–7
4 Psychoneuroimmunology
depression associated with increased methylation of NR3C1 in cord blood mononuclear cells, and the infants with increased methylation exhibited an increased cortisol response to stress at three months of age. These results suggest maternal mood epigenetically modifies fetal NR3C1 to alter the developing HPA axis in a manner to increase infant stress reactivity [18]. Animal models confirm that increased NR3C1 methylation decreases expression of hippocampal GR, dampening GC negative feedback, and increasing stress reactivity [19]. Evidence also supports associations among prenatal mood, placental NR3C1, 11B-HSD2 methylation, and newborn neurobehavior. Infants of mothers reporting prenatal depression, who exhibited greater methylation of placental NR3C1, had poorer self-regulation, more hypotonia, and more lethargy compared to infants of mothers not reporting depression. Whereas, infants of mothers reporting prenatal anxiety exhibited greater methylation of placental 11B-HSD-2 and were more hypotonic compared to infants of mothers not reporting prenatal anxiety [20]. Offspring response to maternal depression may be sex-specific in that maternal prenatal depression predicted increased NF3C1 methylation (a gene dynamically responsive to stress) in buccal cells of two-month old male, but not female infants [21].
Reversal of the effects of maternal prenatal stress A nurturing environment may attenuate the epigenetic impact of maternal depression. Notably, infants of depressed mothers who were more responsive and engaged with their infants had less buccal cell methylation of NR3C1 and 11BHSD2 [22]. Similarly, maternal stroking during the first week of life reversed the elevation of salivary NR3C1 methylation in infants of depressed mothers [23]. Nurturing may foster positive infant behaviors, as infants of depressed mothers who were stroked by their mothers over the first weeks of life exhibited lower emotional reactivity [24]. Interesting preliminary findings from a randomized controlled trial showed a psychosocial intervention targeting high-risk mothers altered the peripheral blood DNA methylome of adult offspring. The intervention aimed to improve maternal mental health and mother–child interactions during pregnancy and up to age two of offspring [25].
Early postnatal stress: preterm infants An adverse early postnatal environment may provoke epigenetic processes that influence development of behavior. A profound example of an adverse postnatal environment is that experienced by hospitalized preterm infants, who endure maternal separation and stressful procedures [26]. Buccal cell DNA from preterm infants, categorized into high versus low-risk neurodevelopment profiles, revealed high-risk infants had more methylation at NR3C1 and less methylation at of HSD11B2, compared to low-risk infants [27]. The high-risk infants had poor Current Opinion in Behavioral Sciences 2019, 28:1–7
self-regulation, were highly excitable, showed poor quality of movement, and exhibited signs of stress. The authors theorized that the methylation changes observed in HSD11B2 represent a compensatory response to reestablish cortisol balance, in the face of higher methylation of NR3C1. Others [8] observed inverse relationships between NR3C1 and HSD11B2 methylation, such that infants with low NR3C1 methylation but high HSD11B2 exhibited different neurobehavioral phenotypes, compared to infants with high NR3C1 methylation but low HSD11B2. A recent systematic review concluded that epigenetic modification of offspring stress-related genes link prenatal and postnatal adverse experiences with developmental trajectories of preterm infants and children [28].
Maternal exposure to violence and trauma Several lines of evidence link maternal exposure to violence or trauma to epigenetic modifications in offspring. Architype studies showed increased NR3C1 exon 1F DNA methylation in blood of children whose mothers experienced; intimate partner violence during pregnancy [29], extreme maternal war-related stress [30], and posttraumatic stress disorder (PTSD) [31]. For adult offspring of Holocaust survivors, 40–60 years of age, paternal PTSD resulted in higher NR3C1 1F methylation, whereas maternal and paternal PTSD showed lower methylation. Further, NR3C1 1F methylation was significantly associated with greater post-dexamethasone cortisol suppression [32], indicating alteration of HPA regulation.
Early life stress, epigenetics, and oxytocin Oxytocin is a key determinant of social behavior, particularly mother–child bonding, and the development of affiliative behavior [33]. Epigenetic alterations to the gene encoding the oxytocin receptor (OXTR) are proposed as a pathway in the intergenerational transmission of maternal stress exposure and offspring psychopathology [34]. For example, increased maternal stressful life events (experienced in the two years preceding pregnancy, including the first trimester), depressive symptoms, and salivary cortisol predicted decreased OXTR methylation in offspring cord blood [35]. The authors speculated that lower OTXR methylation increased OXTR expression, suggesting an epigenetic adaptive response to a potentially stressful postnatal environment. Of note, perception of chronic stress during pregnancy did not relate to newborn OXTR methylation, signifying OXTR methylation is especially sensitive to life-changing events, even when such events occur before pregnancy (i.e. periconceptual events). These findings are consistent with studies showing maternal exposure to more severe traumatic events, such as war-stress [30] or natural disasters [36], alter offspring DNA methylation status. Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC), an ongoing study of children of www.sciencedirect.com
Epigenetics, early life stress, and behavior Janusek, Tell and Mathews 5
14 541 pregnant women in Avon, United Kingdom, suggest that maternal stress and newborn OXTR methylation relate to future behavior problems. Evaluation of a small sample of ALSPAC youth, who had early onset and persistent conduct problems (fighting, stealing), showed higher OXTR methylation at birth associated with higher callous-unemotional traits at age 13, but only in those with low levels of internalizing profiles [37]. These findings are consistent with a prior study showing higher OTXR methylation in blood of 4–16 year old males associated with more conduct problems and callous-unemotional traits, as well as higher circulating oxytocin levels [38]. In contrast, a separate sample of ALSPAC youth, selected for exposure to prenatal and postnatal adversity, showed OXTR methylation predicted resilience to conduct problems [39]. Most recently, methylomic variation across multiple loci in cord blood samples from ALSPAC youth predicted future conduct problems, and some of these loci associated with prenatal adverse exposures [40]. Other behaviors, namely autism spectrum traits at age six, have been linked to interaction between cord blood OXTR methylation and a susceptible genotype (OXTR rs53576) [41]; and childhood anxious behavior has been associated with both early life adversity and OXTR methylation in female young adults, but not males [42]. Mothers with depression exhibit poor nurturing behaviors, which may associate with differential methylation of OXTR. King et al. assessed maternal depression five times across pregnancy and post-partum, with respect to mother and child salivary OXTR methylation at 2.9 years post-partum. Women with persistent depression (across pre-partum and post-partum) had higher OTXR methylation compared to women with no depression or to women with depression during only the pre-partum or post-partum period. No associations were observed with child OXTR methylation. Although preliminary, the findings suggest more enduring, as opposed to episodic, maternal depression alters maternal OXTR methylation, which may compromise maternal nurturing behavior, impairing offspring development [43].
Early life stress, epigenetics, and serotonin The serotonergic system regulates neurobehavioral development, and is associated with stress susceptibility [44] and biopolar disorder [45]. Epigenetic modification to the SLC6A4 gene, which encodes for the serotonin transporter (5-HTT), can influence serotonin neuronal reuptake [46]. Evidence demonstrates both prenatal maternal mood and maternal–infant stress exposure influence methylation status of SLC6A4, such that prenatal depressive mood associates with lower methylation of the SLC6A4 in both maternal blood and offspring cord blood [47]. As well, adult offspring of mothers who experienced prenatal stressful/traumatic events had increased methylation of SLC6A4, with the greater number of prenatal maternal stressful events associating with lower mRNA www.sciencedirect.com
levels [48]. The fetus depends on maternal and placental derived serotonin and alterations of placental serotonergic pathways may influence neurodevelopment. For example, methylation of HTR2A (a gene encoding for a serotonin receptor) in placental tissue was shown to associate with infant attention and quality of movement [49]. Postnatal stress also influences SLC6A4 methylation, as preterm infants experiencing more invasive procedures had higher methylation of SLC6A4 at discharge [50,51], increased socio-emotional stress susceptibility at three months [52], and greater behavioral problems at seven years [53], compared to full-term infants.
Conclusions In conclusion, there is a growing support for early life stressful experiences to engender epigenetic modification, which influence gene expression and future behavior. However, the existing studies have several limitations. The study designs are primarily cross sectional, the sample sizes are relatively small, and most studies fail to correct for multiple comparisons. Further, the timing of prenatal, postnatal, and child/adult assessments varies across studies, making comparisons difficult. All epigenetic analyses were performed in peripheral tissues (peripheral blood, cord blood, saliva, placenta, and buccal cells), and whether similar changes occur within the brain is unclear. Progress in the field will benefit by the conduct of adequately powered longitudinal studies that trace the timing of epigenetic modification with respect to exposure to adversity and the development of behavior. Such a design will strengthen causal inference. There is also need to consider other epigenetic processes, interaction of offspring epigenetic modification with genotype, and paternal effects upon offspring epigenetics (e.g. pre-conception by way of sperm and/or via postnatal fathering). Lastly, early life adversity does not affect all individuals, emphasizing the need to consider the epigenetics of resilience.
Conflict of interest statement Nothing declared.
Acknowledgements Loyola University Chicago HealthEq Research Funds, and the Ruth K. Palmer Memorial Endowment, a gift of Dean Emeritus Gladys Kiniery in memory of her beloved sister, provided funding to support the writing of this manuscript.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest 1.
Chen Z, Li S, Subramaniam S, Shyy JY-J, Chien S: Epigenetic regulation: a new frontier for biomedical engineers. Ann Rev Biomed Eng 2017, 19:195-219.
2.
Bowers ME, Yehuda R: Intergenerational transmission of stress in humans. Neuropsychopharmacology 2016, 41:232-244. Current Opinion in Behavioral Sciences 2019, 28:1–7
6 Psychoneuroimmunology
A review of studies in humans supporting that offspring of stress or trauma exposed parents are at greater risk for psychopathology through epigenetic modification of offspring genes. 3.
4.
5.
Moisiadis VG, Matthews SG: Glucocorticoids and fetal programming part 1: outcomes. Nat Rev Endocrinol 2014, 10:391-402. Palma-Gudiel H, Cordova-Palomera A, Eixarch E, Deuschle M, Fananas L: Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis. Epigenetics 2015, 10:893-902. Sandman CA, Davis EP: Neurobehavioral risk is associated with gestational exposure to stress hormones. Expert Rev Endocrinol Metab 2012, 7:445-459.
Lester BM, Marsit CJ: Epigenetic mechanisms in the placenta related to infant neurodevelopment. Epigenomics 2018, 10:321333. Review of findings from 17 studies, support associations among maternal mood, methylation of glucocorticoid-related genes within the placenta, and indices of infant neurobehavior.
6.
7.
Bromer C, Marsit CJ, Armstrong DA, Padbury JF, Lester B: Genetic and epigenetic variation of the glucocorticoid receptor (NR3C1) in placenta and infant neurobehavior. Dev Psychobiol 2013, 55:673-683.
8.
Appleton AA, Lester BM, Armstrong DA, Lesseur C, Marsit CJ: Examining the joint contribution of placental NR3C1 and HSD11B2 methylation for infant neurobehavior. Psychoneuroendocrinology 2015, 52:32-42.
9.
Paquette AG, Lester BM, Lesseur C, Armstrong DA, Guerin DJ, Appleton AA, Marsit CJ: Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment. Epigenomics 2015, 7:767-779.
10. Conradt E, Fei M, LaGasse L, Tronick E, Guerin D, Gorman D, Marsit CJ, Lester BM: Prenatal predictors of infant selfregulation: the contributions of placental DNA methylation of NR3C1 and neuroendocrine activity. Front Behav Neurosci 2015, 9:130. 11. Rothbart MK, Ellis LK, Posner MI: Temperament and selfregulation. In Handbook of Self-Regulation: Research, Theory, and Applications, vol 2. Edited by Baumeister RF, Vohs KD. Guilford; 2004:357-370. 12. Maccani MA, Padbury JF, Lester BM, Knopik VS, Marsit CJ: Placental miRNA expression profiles are associated with measures of infant neurobehavioral outcomes. Pediatr Res 2013, 74:272-278. 13. Paquette AG, Houseman EA, Green BB, Lesseur C, Armstrong DA, Lester B, Marsit CJ: Regions of variable DNA methylation in human placenta associated with newborn neurobehavior. Epigenetics 2016, 11:603-613. 14. Misra DP, Guyer B, Allston A: Integrated perinatal health framework: a multiple determinants model with a life span approach. Am J Prev Med 2003, 25:65-75. 15. Kramer MS, Seguin L, Lydon J, Goulet L: Socio-economic disparities in pregnancy outcome: why do the poor fare so poorly? Paediatr Perinat Epidemiol 2000, 14:194-210. 16. Appleton AA, Armstrong DA, Lesseur C, Lee J, Padbury JF, Lester BM, Marsit CJ: Patterning in placental 11-B hydroxysteroid dehydrogenase methylation according to prenatal socioeconomic adversity. PLoS One 2013, 8:e74691. 17. Janusek LW, Tell D, Gaylord-Harden N, Mathews HL: Relationship of childhood adversity and neighborhood violence to a proinflammatory phenotype in emerging adult African American men: an epigenetic link. Brain Behav Immun 2017, 60:126-135. 18. 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, 3:97-106. Current Opinion in Behavioral Sciences 2019, 28:1–7
19. 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, 7:847854. 20. Conradt E, Lester BM, Appleton AA, Armstrong DA, Marsit CJ: The roles of DNA methylation of NR3C1 and 11beta-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics 2013, 8:1321-1329. 21. Braithwaite E, Kundakovic M, Ramchandani P, Murphy S, Champagne F: Maternal prenatal depressive symptoms predict infant NR3C1 1F and BDNF IV DNA methylation. Epigenetics 2015, 10:408-417. 22. Conradt E, Hawes K, Guerin D, Armstrong DA, Marsit CJ, Tronick E, Lester BM: The contributions of maternal sensitivity and maternal depressive symptoms to epigenetic processes and neuroendocrine functioning. Child Dev 2016, 87:73-85. Maternal sensitivity reduced the effect of maternal prenatal depressive symptoms on infant DNA methylation of glucocorticoid-related genes. This is an important finding suggesting adverse epigenetic changes can be attenuated. 23. Murgatroyd C, Quinn J, Sharp H, Pickles A, Hill J: Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene. Transl Psychiatry 2015, 5: e560. 24. Sharp H, Pickles A, Meaney M, Marshall K, Tibu F, Hill J: Frequency of infant stroking reported by mothers moderates the effect of prenatal depression on infant behavioural and physiological outcomes. PLoS One 2012, 7:e45446. 25. Olds DL, Eckenrode J, Henderson CR Jr, Kitzman H, Powers J, Cole R, Sidora K, Morris P, Pettitt LM, Luckey D: Long-term effects of home visitation on maternal life course and child abuse and neglect. Fifteen-year follow-up of a randomized trial. JAMA 1997, 278:637-643. 26. Stephens BE, Vohr BR: Neurodevelopmental outcome of the premature infant. Pediatr Clin 2009, 56:631-646. 27. Lester BM, Marsit CJ, Giarraputo J, Hawes K, LaGasse LL, Padbury JF: Neurobehavior related to epigenetic differences in preterm infants. Epigenomics 2015, 7:1123-1136. 28. Provenzi L, Guida E, Montirosso R: Preterm behavioral epigenetics: a systematic review. Neurosci Biobehav Rev 2018, 84:262-271. A systematic review identifying epigenetic modifications in preterm infants related to prenatal and postnatal adverse and protective environments. 29. Radtke KM, Ruf M, Gunter HM, Dohrmann K, Schauer M, Meyer A, Elbert T: Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Transl Psychiatry 2011, 1:e21. 30. Mulligan CJ, D’Errico NC, Stees J, Hughes DA: Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics 2012, 7:853-857. 31. Perroud N, Rutembesa E, Paoloni-Giacobino A, Mutabaruka J, Mutesa L, Stenz L, Malafosse A, Karege F: The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis. World J Biol Psychiatry 2014, 15:334-345. 32. Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine I, Flory JD, Bierer LM, Meaney MJ: Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry 2014, 171:872-880. 33. Ebstein RP, Israel S, Lerer E, Uzefovsky F, Shalev I, Gritsenko I, Riebold M, Salomon S, Yirmiya N: Arginine vasopressin and oxytocin modulate human social behavior. Ann N Y Acad Sci 2009, 1167:87-102. 34. Toepfer P, Heim C, Entringer S, Binder E, Wadhwa P, Buss C: Oxytocin pathways in the intergenerational transmission of maternal early life stress. Neurosci Biobehav Rev 2017, 73:293308. www.sciencedirect.com
Epigenetics, early life stress, and behavior Janusek, Tell and Mathews 7
35. Unternaehrer E, Bolten M, Nast I, Staehli S, Meyer AH, Dempster E, Hellhammer DH, Lieb R, Meinlschmidt G: Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation. Soc Cogn Affect Neurosci 2016, 11:1460-1470. 36. Cao-Lei L, Massart R, Suderman MJ, Machnes Z, Elgbeili G, Laplante DP, Szyf M, King S: DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm. PLoS One 2014, 9:e107653. 37. Cecil CA, Lysenko LJ, Jaffee SR, Pingault JB, Smith RG, Relton CL, Woodward G, McArdle W, Mill J, Barker ED: Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study. Mol Psychiatry 2014, 19:1071-1077. 38. Dadds MR, Moul C, Cauchi A, Dobson-Stone C, Hawes DJ, Brennan J, Ebstein RE: Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy. Dev Psychopathol 2014, 26:33-40. 39. Milaniak I, Cecil CA, Barker ED, Relton CL, Gaunt TR, McArdle W, Jaffee SR: Variation in DNA methylation of the oxytocin receptor gene predicts children’s resilience to prenatal stress. Dev Psychopathol 2017, 29:1663-1674. 40. Cecil CA, Walton E, Jaffee SR, O’Connor T, Maughan B, Relton CL, Smith RG, McArdle W, Gaunt TR, Ouellet-Morin I: Neonatal DNA methylation and early-onset conduct problems: a genomewide, prospective study. Dev Psychopathol 2018, 30:383-397. 41. Rijlaarsdam J, van IJzendoorn MH, Verhulst FC, Jaddoe VW, Felix JF, Tiemeier H, Bakermans-Kranenburg MJ: Prenatal stress exposure, oxytocin receptor gene (OXTR) methylation, and child autistic traits: the moderating role of OXTR rs53576 genotype. Autism Research 2017, 10:430-438. 42. Gouin J-P, Zhou Q, Booij L, Boivin M, Coˆte´ SM, He´bert M, OuelletMorin I, Szyf M, Tremblay RE, Turecki G: Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness. Scientific Reports 2017, 7:7446. 43. King L, Robins S, Chen G, Yerko V, Zhou Y, Nagy C, Feeley N, Gold I, Hayton B, Turecki G et al.: Perinatal depression and DNA methylation of oxytocin-related genes: a study of mothers and their children. Horm Behav 2017, 96:84-94. 44. Lesch KP: When the serotonin transporter gene meets adversity: the contribution of animal models to understanding epigenetic mechanisms in affective disorders and resilience. Curr Top Behav Neurosci 2011, 7:251-280. 45. Carrard A, Salzmann A, Malafosse A, Karege F: Increased DNA methylation status of the serotonin receptor 5HTR1A gene
www.sciencedirect.com
promoter in schizophrenia and bipolar disorder. J Affect Disord 2011, 132:450-453. 46. Provenzi L, Giorda R, Beri S, Montirosso R: SLC6A4 methylation as an epigenetic marker of life adversity exposures in humans: a systematic review of literature. Neurosci Biobehav Rev 2016, 71:7-20. 47. Devlin AM, Brain U, Austin J, Oberlander TF: Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS One 2010, 5: e12201. 48. Wankerl M, Miller R, Kirschbaum C, Hennig J, Stalder T, Alexander N: Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles. Transl Psychiatry 2014, 4:e402. 49. Paquette AG, Lesseur C, Armstrong DA, Koestler DC, Appleton AA, Lester BM, Marsit CJ: Placental HTR2A methylation is associated with infant neurobehavioral outcomes. Epigenetics 2013, 8:796-801. 50. Provenzi L, Fumagalli M, Giorda R, Morandi F, Sirgiovanni I, Pozzoli U, Mosca F, Borgatti R, Montirosso R: Maternal sensitivity buffers the association between SLC6A4 methylation and socio-emotional stress response in 3-monthold full term, but not very preterm infants. Front Psychiatry 2017, 8:171. 51. Fumagalli M, Provenzi L, De Carli P, Dessimone F, Sirgiovanni I, Giorda R, Cinnante C, Squarcina L, Pozzoli U, Triulzi F et al.: From early stress to 12-month development in very preterm infants: preliminary findings on epigenetic mechanisms and brain growth. PLoS One 2018, 13:e0190602. Higher stress due to Neonatal Intensive Care Unit (NICU) experience associated with greater increase inSLC6A4 (serotonin transporter gene) and reduced anterior temporal lobe (ATL) volume in preterm infants at NICU discharge. Exploratory mediational analysis suggested reduced ATL volume mediated the association between stress-induced change in SLC6A4 methylation at discharge and lower socio-emotional development at 12 months. 52. Montirosso R, Provenzi L, Fumagalli M, Sirgiovanni I, Giorda R, Pozzoli U, Beri S, Menozzi G, Tronick E, Morandi F et al.: Serotonin transporter gene (SLC6A4) methylation associates with neonatal intensive care unit stay and 3-month-old temperament in preterm infants. Child Dev 2016, 87:38-48. 53. Chau CMY, Ranger M, Sulistyoningrum D, Devlin AM, Oberlander TF, Grunau RE: Neonatal pain and COMT Val158Met genotype in relation to serotonin transporter (SLC6A4) promoter methylation in very preterm children at school age. Front Behav Neurosci 2014, 8:409.
Current Opinion in Behavioral Sciences 2019, 28:1–7
ScienceDirect Epigenetic perpetuation of the impact of early life stress on behavior Linda Witek Janusek1, Dina Tell1 and Herbert L Mathews2 There is growing support for epigenetic perpetuation of early life stressful experiences on offspring behavior. Evidence primarily exists for maternal psychosocial experiences (i.e. mood and exposure to stress, adversity, or trauma) to associate with epigenetic modification to offspring genes involved in neurobehavioral pathways (i.e. glucocorticoid, oxytocin, and serotonin system genes). Such epigenetic modifications associate with altered infant neurobehavioral developmental profiles, stress reactivity, and maladaptive behaviors observed in childhood and/or adolescence. Epigenetic transmission of adverse early life experiences to the offspring genome most often occurs during the prenatal and early postnatal periods, when developing systems are more sensitive to environmental signals. Emerging work suggests interventions that foster positive maternal–infant interactions may attenuate the epigenetic impact of early life stress. Addresses 1 Marcella Niehoff School of Nursing, Department of Health Promotion, Loyola University Chicago, Health Science Division, 2160 South First Ave., Maywood, IL 60153, United States 2 Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Health Science Division, 2160 South First Ave., Maywood, IL 60153, United States Corresponding author: Janusek, Linda Witek ([email protected])
Current Opinion in Behavioral Sciences 2019, 28C:1–7 This review comes from a themed issue on Psychoneuroimmunology Edited by Suzanne Segerstrom and Deborah Hodgson
https://doi.org/10.1016/j.cobeha.2019.01.004 2352-1546/ã 2018 Elsevier Ltd. All rights reserved.
structure to affect gene expression independent of a change in DNA sequence. Although DNA encodes for genes using a sequence of nucleotide bases (adenine, thymine, guanine, and cytosine), epigenetic modifications influence the level of gene expression, either amplifying or diminishing expression. A unifying epigenetic concept is phenotypic plasticity, wherein a cell’s epigenetic signature (i.e. epigenome) is modifiable by the environment. Thus, an epigenetic signature provides a layer of variation that may mediate the relationship between genotype and environmental exposure. Epigenetic modifications can be passed across generations of both somatic and germline cells, allowing durable (and potentially cross-generational) influences. For a recent review, see Ref. [1]. Since epigenetic processes are sensitive to the environment, including the psychosocial environment, epigenetics provides a framework to understand the biological mechanisms, by which early life environmental signals influence future behavior. The discovery that epigenetic processes translate the early psychosocial environment to the genome is one of the most intriguing lines of investigation in contemporary biology. This review will focus on recent investigations in humans, which examine epigenetic processes as a mechanism, by which early life experiences influence offspring behavior. Most of such investigations have focused on the consequence of maternal prenatal experiences (i.e. maternal mood, and exposure to stress, trauma, or social adversity) and/or the impact of an adverse early postnatal environment [2]. Although paternal influences on offspring behavioral development may occur through epigenetic modification, either to sperm DNA or through fathers’ caregiving, such research is limited. Figure 2 describes the framework guiding this review.
Early life stress and stress-related genes Introduction The early life psychosocial environment is a powerful determinant of development. An adverse intrauterine environment, as well as a non-nurturing postnatal environment, can exert enduring biological effects that shape future behavior. A key question is what biological process perpetuates the impact of these early experiences on future behavior? One process by which this may occur is through epigenetic modification of the offspring genome. Epigenetic modification refers to a variety of processes, illustrated in Figure 1 that modify chromatin www.sciencedirect.com
Early life stress may influence offspring behavior through epigenetic processes that affect developing stress response systems, particularly the hypothalamic– pituitary–adrenal (HPA) axis. Stress activation of the HPA axis results in the release of cortisol, the body’s main glucocorticoid (GC). Cortisol plays a key role in fetal brain development, and accordingly, negative feedback mechanisms tightly regulate cortisol levels. Excessive exposure to cortisol, due to epigenetic alterations of GC-related genes, is linked to poor neurobehavioral outcomes [3]. Of GC-related genes, the GC receptor (GR) (Nuclear Receptor Subfamily 3 Group C Member 1, Current Opinion in Behavioral Sciences 2019, 28:1–7
2 Psychoneuroimmunology
Figure 1
DNA methylation
Genes
DNase I hypersensitive sites
Chromatin
RNA
Histone Modifications
Current Opinion in Behavioral Sciences
Key epigenetic processes that influence gene expression. Epigenetics refers to heritable phenotypic changes in gene expression that do not involve alterations in the sequence of DNA. Several epigenetic processes regulate gene expression and genome activity. DNA methylation is the most extensively studied. DNA methylation attaches a methyl group to DNA, primarily at a cytosine base adjacent to a guanine residue, producing 5-methylcytosine (other chemical modifications of cytosine bases in DNA have also been described). In broad terms the presence of 5methylcytosine often represses DNA transcription. Another epigenetic process regulating gene expression and genome activity is histone modification. DNA is wrapped around histone proteins creating nucleosomes that can be chemically modified to alter gene expression. A number of histone post-translational modifications (e.g. lysine acetylation) can change chromatin structure or recruit transcriptional cofactors to DNA that increase gene expression. Alternatively, modifications (e.g. lysine methylation) can act to repress or reduce gene expression (e.g. in heterochromatin). Non-coding RNA molecules can also act epigenetically. These are small or long RNA molecules that do not code for a protein, but rather function to regulate gene expression. These non-coding RNA molecules are not DNA sequence-dependent, so the majority do not rely on a nucleotide sequence that is complimentary to a specific DNA or RNA region in order to function. Non-coding RNAs are examples of RNA classes that are present in sperm and can act epigenetically to affect subsequent generations. For a recent review see Ref. [1]. Illustration from the National Institutes of Health Roadmap Epigenomics http://www.roadmapepigenomics.org/.
NR3C1), has been the most explored. Although several different NR3C1 regions have been investigated, exon 1F of NR3C1 has been consistently shown to be epigenetically influenced by stress. Exon 1F contains a DNA sequence element that encodes a methylation-sensitive binding site for the neural activity-regulated transcription activator, NGF1A/EGR1. Reduced transcription of NR3C1 due to increased methylation of this binding site diminishes GC-GR mediated negative feedback within the hypothalamus. As a result, inappropriate elevations of cortisol can impair development of offspring neurobehavioral pathways. For example, meta-analysis of mothers (977 subjects across seven studies) who reported anxiousdepressive behavior or exposure to violence during pregnancy demonstrated correlations among increased offspring DNA methylation and prenatal stress at CpG positon 36 of NR3C1 1F [4]. Adjacent positions 35, 37, 38, or 39 and other positions did not correlate with maternal stress. It is important to note that differences in DNA methylation technologies or individual differences in the psychosocial circumstances may account for the lack of correlations among these and other CpG residues across investigations. Although results are Current Opinion in Behavioral Sciences 2019, 28:1–7
mixed, there is a growing support for a connection among NR3C1 methylation, early life experiences, and behavior in humans.
Early life stress and epigenetic modification of placental GC-related genes The placenta regulates the intrauterine environment, protecting the fetus from environmental insults. Stress exposure may induce epigenetic alterations of placental GC-related genes, HSD11B2 and NR3C1. Both genes are highly expressed in the placenta and associate with perinatal stress. HSD11B2 encodes the enzyme, 11-beta hydroxysteroid dehydrogenase type 2, which inactivates cortisol, thereby shielding the fetus from the damaging effects of excess cortisol. However, the capacity for HSD11B2 to buffer excess cortisol is limited, allowing maternal stress to expose the fetus to excess cortisol [5]. Two categories of investigations link epigenetic modification of placental NR3C1 and HSD11B2 to poor neurobehavioral outcomes: (1) those demonstrating relationships between epigenetic modification of placental genes and infant neurodevelopment; and (2) those suggesting placental epigenetic mechanisms mediate the effect of www.sciencedirect.com
Epigenetics, early life stress, and behavior Janusek, Tell and Mathews 3
Figure 2 Life stress, adversity, trauma
Preconception
Intrauterine
Infancy
Childhood/ adolescence
Epigenetic processes
Behavioral phenotype Current Opinion in Behavioral Sciences
Epigenetic perpetuation of the impact of early life stress, adversity and trauma on behavioral phenotype. Epigenetic processes provide a framework for understanding the biological mechanisms by which pre-natal and post-natal environmental events influence offspring behavior. Epigenetic modifications, such as DNA methylation, can be passed on during cell division and confer long-term phenotypic changes. Epigenetic processes are sensitive to the environment. As a result, environmental stress, adversity, or trauma can trigger epigenetic modification across the developmental spectrum, from parental exposures that affect germ cells (pre-conception) to offspring exposures stemming from the intrauterine and/or early postnatal environment. During development, there are critical biological windows in which environmental influences are more likely to alter epigenetic processes and influence behavioral phenotype. Behavioral epigenetics is a field of study that investigates antecedents (e.g. stress, adversity, and trauma) and outcomes of epigenetic modifications in genes (e.g. stress-related genes) involved in the development of behavior.
prenatal factors on infant neurodevelopment [6]. Common infant neurobehaviors associated with differential methylation of placental NR3C1 are attention and quality of movement [7]. Moreover, interactions between placental NR3C1 and HSD11B2 methylation associate with distinct domains of infant neurobehavioral phenotypes [8]. For example, methylation of NR3C1 associates with a reactive, poorly regulated behavioral profile; while methylation of HSD11B2 reduces risk for this behavior [9]. A critical question is whether epigenetic changes to GCrelated genes associate not only with infant neurobehavior, but also with infant stress reactivity. This was demonstrated when greater methylation of placental NR3C1 was shown to predict greater infant cortisol stress reactivity, as well as infant self-regulation at five months of age [10]. Both a robust HPA stress response and infant ability to self-regulate (i.e. organize behavior) in response to stress are critical developmental milestones that forecast future psychological health [11]. Beyond methylation analysis, other epigenetic processes may be operative, but not as well investigated. For example, decreased expression of microRNAs (miRNAs) has been associated with infant attention and quality of movement. Specifically, miRNAs from term placentas exhibited increased miR-16 expression that negatively associated with reduced attention, while increased miR14a and increased miR-182 associated with better quality of movement [12]. These miRNAs target multiple genes, www.sciencedirect.com
including the serotonin receptor. Using an epigenomewide approach, variable methylation in 50 placental genes associated with infant neurobehavior (attention, lethargy, quality of movement, and arousal) has been reported. Gene ontology analysis supports a role for these genes in brain development [13].
Maternal social adversity and mood Social adversity may influence pregnancy outcomes through epigenetic processes, exerting effects before pregnancy, during pregnancy, or throughout the early caregiving years [14] [15]. For instance, infants of mothers experiencing socioeconomic adversity during pregnancy exhibited decreased placental HSD11B2 methylation, most evident in males [16]. Reduced methylation of placental HSD11B2 theoretically increases transcription of this enzyme, enhancing fetal capacity to inactivate excess maternal cortisol resulting from socioeconomic stress. Possibly, the chronicity of socioeconomic stress may foster an ‘adaptive epigenetic profile,’ which differs from that resulting from acute or traumatic stressors. Emerging work suggests epigenetic processes resulting from adverse early life adverse social conditions contribute to altered stress reactivity, and risk for health disparity [17]. An important line of investigation is whether maternal mood engenders epigenetic modification of offspring genes. A seminal study demonstrated maternal Current Opinion in Behavioral Sciences 2019, 28:1–7
4 Psychoneuroimmunology
depression associated with increased methylation of NR3C1 in cord blood mononuclear cells, and the infants with increased methylation exhibited an increased cortisol response to stress at three months of age. These results suggest maternal mood epigenetically modifies fetal NR3C1 to alter the developing HPA axis in a manner to increase infant stress reactivity [18]. Animal models confirm that increased NR3C1 methylation decreases expression of hippocampal GR, dampening GC negative feedback, and increasing stress reactivity [19]. Evidence also supports associations among prenatal mood, placental NR3C1, 11B-HSD2 methylation, and newborn neurobehavior. Infants of mothers reporting prenatal depression, who exhibited greater methylation of placental NR3C1, had poorer self-regulation, more hypotonia, and more lethargy compared to infants of mothers not reporting depression. Whereas, infants of mothers reporting prenatal anxiety exhibited greater methylation of placental 11B-HSD-2 and were more hypotonic compared to infants of mothers not reporting prenatal anxiety [20]. Offspring response to maternal depression may be sex-specific in that maternal prenatal depression predicted increased NF3C1 methylation (a gene dynamically responsive to stress) in buccal cells of two-month old male, but not female infants [21].
Reversal of the effects of maternal prenatal stress A nurturing environment may attenuate the epigenetic impact of maternal depression. Notably, infants of depressed mothers who were more responsive and engaged with their infants had less buccal cell methylation of NR3C1 and 11BHSD2 [22]. Similarly, maternal stroking during the first week of life reversed the elevation of salivary NR3C1 methylation in infants of depressed mothers [23]. Nurturing may foster positive infant behaviors, as infants of depressed mothers who were stroked by their mothers over the first weeks of life exhibited lower emotional reactivity [24]. Interesting preliminary findings from a randomized controlled trial showed a psychosocial intervention targeting high-risk mothers altered the peripheral blood DNA methylome of adult offspring. The intervention aimed to improve maternal mental health and mother–child interactions during pregnancy and up to age two of offspring [25].
Early postnatal stress: preterm infants An adverse early postnatal environment may provoke epigenetic processes that influence development of behavior. A profound example of an adverse postnatal environment is that experienced by hospitalized preterm infants, who endure maternal separation and stressful procedures [26]. Buccal cell DNA from preterm infants, categorized into high versus low-risk neurodevelopment profiles, revealed high-risk infants had more methylation at NR3C1 and less methylation at of HSD11B2, compared to low-risk infants [27]. The high-risk infants had poor Current Opinion in Behavioral Sciences 2019, 28:1–7
self-regulation, were highly excitable, showed poor quality of movement, and exhibited signs of stress. The authors theorized that the methylation changes observed in HSD11B2 represent a compensatory response to reestablish cortisol balance, in the face of higher methylation of NR3C1. Others [8] observed inverse relationships between NR3C1 and HSD11B2 methylation, such that infants with low NR3C1 methylation but high HSD11B2 exhibited different neurobehavioral phenotypes, compared to infants with high NR3C1 methylation but low HSD11B2. A recent systematic review concluded that epigenetic modification of offspring stress-related genes link prenatal and postnatal adverse experiences with developmental trajectories of preterm infants and children [28].
Maternal exposure to violence and trauma Several lines of evidence link maternal exposure to violence or trauma to epigenetic modifications in offspring. Architype studies showed increased NR3C1 exon 1F DNA methylation in blood of children whose mothers experienced; intimate partner violence during pregnancy [29], extreme maternal war-related stress [30], and posttraumatic stress disorder (PTSD) [31]. For adult offspring of Holocaust survivors, 40–60 years of age, paternal PTSD resulted in higher NR3C1 1F methylation, whereas maternal and paternal PTSD showed lower methylation. Further, NR3C1 1F methylation was significantly associated with greater post-dexamethasone cortisol suppression [32], indicating alteration of HPA regulation.
Early life stress, epigenetics, and oxytocin Oxytocin is a key determinant of social behavior, particularly mother–child bonding, and the development of affiliative behavior [33]. Epigenetic alterations to the gene encoding the oxytocin receptor (OXTR) are proposed as a pathway in the intergenerational transmission of maternal stress exposure and offspring psychopathology [34]. For example, increased maternal stressful life events (experienced in the two years preceding pregnancy, including the first trimester), depressive symptoms, and salivary cortisol predicted decreased OXTR methylation in offspring cord blood [35]. The authors speculated that lower OTXR methylation increased OXTR expression, suggesting an epigenetic adaptive response to a potentially stressful postnatal environment. Of note, perception of chronic stress during pregnancy did not relate to newborn OXTR methylation, signifying OXTR methylation is especially sensitive to life-changing events, even when such events occur before pregnancy (i.e. periconceptual events). These findings are consistent with studies showing maternal exposure to more severe traumatic events, such as war-stress [30] or natural disasters [36], alter offspring DNA methylation status. Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC), an ongoing study of children of www.sciencedirect.com
Epigenetics, early life stress, and behavior Janusek, Tell and Mathews 5
14 541 pregnant women in Avon, United Kingdom, suggest that maternal stress and newborn OXTR methylation relate to future behavior problems. Evaluation of a small sample of ALSPAC youth, who had early onset and persistent conduct problems (fighting, stealing), showed higher OXTR methylation at birth associated with higher callous-unemotional traits at age 13, but only in those with low levels of internalizing profiles [37]. These findings are consistent with a prior study showing higher OTXR methylation in blood of 4–16 year old males associated with more conduct problems and callous-unemotional traits, as well as higher circulating oxytocin levels [38]. In contrast, a separate sample of ALSPAC youth, selected for exposure to prenatal and postnatal adversity, showed OXTR methylation predicted resilience to conduct problems [39]. Most recently, methylomic variation across multiple loci in cord blood samples from ALSPAC youth predicted future conduct problems, and some of these loci associated with prenatal adverse exposures [40]. Other behaviors, namely autism spectrum traits at age six, have been linked to interaction between cord blood OXTR methylation and a susceptible genotype (OXTR rs53576) [41]; and childhood anxious behavior has been associated with both early life adversity and OXTR methylation in female young adults, but not males [42]. Mothers with depression exhibit poor nurturing behaviors, which may associate with differential methylation of OXTR. King et al. assessed maternal depression five times across pregnancy and post-partum, with respect to mother and child salivary OXTR methylation at 2.9 years post-partum. Women with persistent depression (across pre-partum and post-partum) had higher OTXR methylation compared to women with no depression or to women with depression during only the pre-partum or post-partum period. No associations were observed with child OXTR methylation. Although preliminary, the findings suggest more enduring, as opposed to episodic, maternal depression alters maternal OXTR methylation, which may compromise maternal nurturing behavior, impairing offspring development [43].
Early life stress, epigenetics, and serotonin The serotonergic system regulates neurobehavioral development, and is associated with stress susceptibility [44] and biopolar disorder [45]. Epigenetic modification to the SLC6A4 gene, which encodes for the serotonin transporter (5-HTT), can influence serotonin neuronal reuptake [46]. Evidence demonstrates both prenatal maternal mood and maternal–infant stress exposure influence methylation status of SLC6A4, such that prenatal depressive mood associates with lower methylation of the SLC6A4 in both maternal blood and offspring cord blood [47]. As well, adult offspring of mothers who experienced prenatal stressful/traumatic events had increased methylation of SLC6A4, with the greater number of prenatal maternal stressful events associating with lower mRNA www.sciencedirect.com
levels [48]. The fetus depends on maternal and placental derived serotonin and alterations of placental serotonergic pathways may influence neurodevelopment. For example, methylation of HTR2A (a gene encoding for a serotonin receptor) in placental tissue was shown to associate with infant attention and quality of movement [49]. Postnatal stress also influences SLC6A4 methylation, as preterm infants experiencing more invasive procedures had higher methylation of SLC6A4 at discharge [50,51], increased socio-emotional stress susceptibility at three months [52], and greater behavioral problems at seven years [53], compared to full-term infants.
Conclusions In conclusion, there is a growing support for early life stressful experiences to engender epigenetic modification, which influence gene expression and future behavior. However, the existing studies have several limitations. The study designs are primarily cross sectional, the sample sizes are relatively small, and most studies fail to correct for multiple comparisons. Further, the timing of prenatal, postnatal, and child/adult assessments varies across studies, making comparisons difficult. All epigenetic analyses were performed in peripheral tissues (peripheral blood, cord blood, saliva, placenta, and buccal cells), and whether similar changes occur within the brain is unclear. Progress in the field will benefit by the conduct of adequately powered longitudinal studies that trace the timing of epigenetic modification with respect to exposure to adversity and the development of behavior. Such a design will strengthen causal inference. There is also need to consider other epigenetic processes, interaction of offspring epigenetic modification with genotype, and paternal effects upon offspring epigenetics (e.g. pre-conception by way of sperm and/or via postnatal fathering). Lastly, early life adversity does not affect all individuals, emphasizing the need to consider the epigenetics of resilience.
Conflict of interest statement Nothing declared.
Acknowledgements Loyola University Chicago HealthEq Research Funds, and the Ruth K. Palmer Memorial Endowment, a gift of Dean Emeritus Gladys Kiniery in memory of her beloved sister, provided funding to support the writing of this manuscript.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest 1.
Chen Z, Li S, Subramaniam S, Shyy JY-J, Chien S: Epigenetic regulation: a new frontier for biomedical engineers. Ann Rev Biomed Eng 2017, 19:195-219.
2.
Bowers ME, Yehuda R: Intergenerational transmission of stress in humans. Neuropsychopharmacology 2016, 41:232-244. Current Opinion in Behavioral Sciences 2019, 28:1–7
6 Psychoneuroimmunology
A review of studies in humans supporting that offspring of stress or trauma exposed parents are at greater risk for psychopathology through epigenetic modification of offspring genes. 3.
4.
5.
Moisiadis VG, Matthews SG: Glucocorticoids and fetal programming part 1: outcomes. Nat Rev Endocrinol 2014, 10:391-402. Palma-Gudiel H, Cordova-Palomera A, Eixarch E, Deuschle M, Fananas L: Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis. Epigenetics 2015, 10:893-902. Sandman CA, Davis EP: Neurobehavioral risk is associated with gestational exposure to stress hormones. Expert Rev Endocrinol Metab 2012, 7:445-459.
Lester BM, Marsit CJ: Epigenetic mechanisms in the placenta related to infant neurodevelopment. Epigenomics 2018, 10:321333. Review of findings from 17 studies, support associations among maternal mood, methylation of glucocorticoid-related genes within the placenta, and indices of infant neurobehavior.
6.
7.
Bromer C, Marsit CJ, Armstrong DA, Padbury JF, Lester B: Genetic and epigenetic variation of the glucocorticoid receptor (NR3C1) in placenta and infant neurobehavior. Dev Psychobiol 2013, 55:673-683.
8.
Appleton AA, Lester BM, Armstrong DA, Lesseur C, Marsit CJ: Examining the joint contribution of placental NR3C1 and HSD11B2 methylation for infant neurobehavior. Psychoneuroendocrinology 2015, 52:32-42.
9.
Paquette AG, Lester BM, Lesseur C, Armstrong DA, Guerin DJ, Appleton AA, Marsit CJ: Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment. Epigenomics 2015, 7:767-779.
10. Conradt E, Fei M, LaGasse L, Tronick E, Guerin D, Gorman D, Marsit CJ, Lester BM: Prenatal predictors of infant selfregulation: the contributions of placental DNA methylation of NR3C1 and neuroendocrine activity. Front Behav Neurosci 2015, 9:130. 11. Rothbart MK, Ellis LK, Posner MI: Temperament and selfregulation. In Handbook of Self-Regulation: Research, Theory, and Applications, vol 2. Edited by Baumeister RF, Vohs KD. Guilford; 2004:357-370. 12. Maccani MA, Padbury JF, Lester BM, Knopik VS, Marsit CJ: Placental miRNA expression profiles are associated with measures of infant neurobehavioral outcomes. Pediatr Res 2013, 74:272-278. 13. Paquette AG, Houseman EA, Green BB, Lesseur C, Armstrong DA, Lester B, Marsit CJ: Regions of variable DNA methylation in human placenta associated with newborn neurobehavior. Epigenetics 2016, 11:603-613. 14. Misra DP, Guyer B, Allston A: Integrated perinatal health framework: a multiple determinants model with a life span approach. Am J Prev Med 2003, 25:65-75. 15. Kramer MS, Seguin L, Lydon J, Goulet L: Socio-economic disparities in pregnancy outcome: why do the poor fare so poorly? Paediatr Perinat Epidemiol 2000, 14:194-210. 16. Appleton AA, Armstrong DA, Lesseur C, Lee J, Padbury JF, Lester BM, Marsit CJ: Patterning in placental 11-B hydroxysteroid dehydrogenase methylation according to prenatal socioeconomic adversity. PLoS One 2013, 8:e74691. 17. Janusek LW, Tell D, Gaylord-Harden N, Mathews HL: Relationship of childhood adversity and neighborhood violence to a proinflammatory phenotype in emerging adult African American men: an epigenetic link. Brain Behav Immun 2017, 60:126-135. 18. 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, 3:97-106. Current Opinion in Behavioral Sciences 2019, 28:1–7
19. 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, 7:847854. 20. Conradt E, Lester BM, Appleton AA, Armstrong DA, Marsit CJ: The roles of DNA methylation of NR3C1 and 11beta-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics 2013, 8:1321-1329. 21. Braithwaite E, Kundakovic M, Ramchandani P, Murphy S, Champagne F: Maternal prenatal depressive symptoms predict infant NR3C1 1F and BDNF IV DNA methylation. Epigenetics 2015, 10:408-417. 22. Conradt E, Hawes K, Guerin D, Armstrong DA, Marsit CJ, Tronick E, Lester BM: The contributions of maternal sensitivity and maternal depressive symptoms to epigenetic processes and neuroendocrine functioning. Child Dev 2016, 87:73-85. Maternal sensitivity reduced the effect of maternal prenatal depressive symptoms on infant DNA methylation of glucocorticoid-related genes. This is an important finding suggesting adverse epigenetic changes can be attenuated. 23. Murgatroyd C, Quinn J, Sharp H, Pickles A, Hill J: Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene. Transl Psychiatry 2015, 5: e560. 24. Sharp H, Pickles A, Meaney M, Marshall K, Tibu F, Hill J: Frequency of infant stroking reported by mothers moderates the effect of prenatal depression on infant behavioural and physiological outcomes. PLoS One 2012, 7:e45446. 25. Olds DL, Eckenrode J, Henderson CR Jr, Kitzman H, Powers J, Cole R, Sidora K, Morris P, Pettitt LM, Luckey D: Long-term effects of home visitation on maternal life course and child abuse and neglect. Fifteen-year follow-up of a randomized trial. JAMA 1997, 278:637-643. 26. Stephens BE, Vohr BR: Neurodevelopmental outcome of the premature infant. Pediatr Clin 2009, 56:631-646. 27. Lester BM, Marsit CJ, Giarraputo J, Hawes K, LaGasse LL, Padbury JF: Neurobehavior related to epigenetic differences in preterm infants. Epigenomics 2015, 7:1123-1136. 28. Provenzi L, Guida E, Montirosso R: Preterm behavioral epigenetics: a systematic review. Neurosci Biobehav Rev 2018, 84:262-271. A systematic review identifying epigenetic modifications in preterm infants related to prenatal and postnatal adverse and protective environments. 29. Radtke KM, Ruf M, Gunter HM, Dohrmann K, Schauer M, Meyer A, Elbert T: Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Transl Psychiatry 2011, 1:e21. 30. Mulligan CJ, D’Errico NC, Stees J, Hughes DA: Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics 2012, 7:853-857. 31. Perroud N, Rutembesa E, Paoloni-Giacobino A, Mutabaruka J, Mutesa L, Stenz L, Malafosse A, Karege F: The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis. World J Biol Psychiatry 2014, 15:334-345. 32. Yehuda R, Daskalakis NP, Lehrner A, Desarnaud F, Bader HN, Makotkine I, Flory JD, Bierer LM, Meaney MJ: Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry 2014, 171:872-880. 33. Ebstein RP, Israel S, Lerer E, Uzefovsky F, Shalev I, Gritsenko I, Riebold M, Salomon S, Yirmiya N: Arginine vasopressin and oxytocin modulate human social behavior. Ann N Y Acad Sci 2009, 1167:87-102. 34. Toepfer P, Heim C, Entringer S, Binder E, Wadhwa P, Buss C: Oxytocin pathways in the intergenerational transmission of maternal early life stress. Neurosci Biobehav Rev 2017, 73:293308. www.sciencedirect.com
Epigenetics, early life stress, and behavior Janusek, Tell and Mathews 7
35. Unternaehrer E, Bolten M, Nast I, Staehli S, Meyer AH, Dempster E, Hellhammer DH, Lieb R, Meinlschmidt G: Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation. Soc Cogn Affect Neurosci 2016, 11:1460-1470. 36. Cao-Lei L, Massart R, Suderman MJ, Machnes Z, Elgbeili G, Laplante DP, Szyf M, King S: DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm. PLoS One 2014, 9:e107653. 37. Cecil CA, Lysenko LJ, Jaffee SR, Pingault JB, Smith RG, Relton CL, Woodward G, McArdle W, Mill J, Barker ED: Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study. Mol Psychiatry 2014, 19:1071-1077. 38. Dadds MR, Moul C, Cauchi A, Dobson-Stone C, Hawes DJ, Brennan J, Ebstein RE: Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy. Dev Psychopathol 2014, 26:33-40. 39. Milaniak I, Cecil CA, Barker ED, Relton CL, Gaunt TR, McArdle W, Jaffee SR: Variation in DNA methylation of the oxytocin receptor gene predicts children’s resilience to prenatal stress. Dev Psychopathol 2017, 29:1663-1674. 40. Cecil CA, Walton E, Jaffee SR, O’Connor T, Maughan B, Relton CL, Smith RG, McArdle W, Gaunt TR, Ouellet-Morin I: Neonatal DNA methylation and early-onset conduct problems: a genomewide, prospective study. Dev Psychopathol 2018, 30:383-397. 41. Rijlaarsdam J, van IJzendoorn MH, Verhulst FC, Jaddoe VW, Felix JF, Tiemeier H, Bakermans-Kranenburg MJ: Prenatal stress exposure, oxytocin receptor gene (OXTR) methylation, and child autistic traits: the moderating role of OXTR rs53576 genotype. Autism Research 2017, 10:430-438. 42. Gouin J-P, Zhou Q, Booij L, Boivin M, Coˆte´ SM, He´bert M, OuelletMorin I, Szyf M, Tremblay RE, Turecki G: Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness. Scientific Reports 2017, 7:7446. 43. King L, Robins S, Chen G, Yerko V, Zhou Y, Nagy C, Feeley N, Gold I, Hayton B, Turecki G et al.: Perinatal depression and DNA methylation of oxytocin-related genes: a study of mothers and their children. Horm Behav 2017, 96:84-94. 44. Lesch KP: When the serotonin transporter gene meets adversity: the contribution of animal models to understanding epigenetic mechanisms in affective disorders and resilience. Curr Top Behav Neurosci 2011, 7:251-280. 45. Carrard A, Salzmann A, Malafosse A, Karege F: Increased DNA methylation status of the serotonin receptor 5HTR1A gene
www.sciencedirect.com
promoter in schizophrenia and bipolar disorder. J Affect Disord 2011, 132:450-453. 46. Provenzi L, Giorda R, Beri S, Montirosso R: SLC6A4 methylation as an epigenetic marker of life adversity exposures in humans: a systematic review of literature. Neurosci Biobehav Rev 2016, 71:7-20. 47. Devlin AM, Brain U, Austin J, Oberlander TF: Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS One 2010, 5: e12201. 48. Wankerl M, Miller R, Kirschbaum C, Hennig J, Stalder T, Alexander N: Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles. Transl Psychiatry 2014, 4:e402. 49. Paquette AG, Lesseur C, Armstrong DA, Koestler DC, Appleton AA, Lester BM, Marsit CJ: Placental HTR2A methylation is associated with infant neurobehavioral outcomes. Epigenetics 2013, 8:796-801. 50. Provenzi L, Fumagalli M, Giorda R, Morandi F, Sirgiovanni I, Pozzoli U, Mosca F, Borgatti R, Montirosso R: Maternal sensitivity buffers the association between SLC6A4 methylation and socio-emotional stress response in 3-monthold full term, but not very preterm infants. Front Psychiatry 2017, 8:171. 51. Fumagalli M, Provenzi L, De Carli P, Dessimone F, Sirgiovanni I, Giorda R, Cinnante C, Squarcina L, Pozzoli U, Triulzi F et al.: From early stress to 12-month development in very preterm infants: preliminary findings on epigenetic mechanisms and brain growth. PLoS One 2018, 13:e0190602. Higher stress due to Neonatal Intensive Care Unit (NICU) experience associated with greater increase inSLC6A4 (serotonin transporter gene) and reduced anterior temporal lobe (ATL) volume in preterm infants at NICU discharge. Exploratory mediational analysis suggested reduced ATL volume mediated the association between stress-induced change in SLC6A4 methylation at discharge and lower socio-emotional development at 12 months. 52. Montirosso R, Provenzi L, Fumagalli M, Sirgiovanni I, Giorda R, Pozzoli U, Beri S, Menozzi G, Tronick E, Morandi F et al.: Serotonin transporter gene (SLC6A4) methylation associates with neonatal intensive care unit stay and 3-month-old temperament in preterm infants. Child Dev 2016, 87:38-48. 53. Chau CMY, Ranger M, Sulistyoningrum D, Devlin AM, Oberlander TF, Grunau RE: Neonatal pain and COMT Val158Met genotype in relation to serotonin transporter (SLC6A4) promoter methylation in very preterm children at school age. Front Behav Neurosci 2014, 8:409.
Current Opinion in Behavioral Sciences 2019, 28:1–7