Biological Embedding Research Articles

Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus

BackgroundEpigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported.ResultsWe repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1 h, 3 h, 6 h), which returned to baseline levels within 23 h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS.ConclusionOur study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure.

The Consequences of Foster Care Versus Institutional Care in Early Childhood on Adolescent Cardiometabolic and Immune Markers: Results From a Randomized Controlled Trial.

Children exposed to institutional rearing often exhibit problems across a broad array of developmental domains. We compared the consequences of long-term, high-quality foster care versus standard institution-based care, which began in early childhood on cardiometabolic and immune markers assessed at the time of adolescence. The Bucharest Early Intervention Project is a longitudinal investigation of children institutionalized during early childhood (ages 6 to 30 months at baseline) who were subsequently randomized to either high-quality foster care or continued institutional care. At the age of 16 years, 127 respondents participated in a biomarker collection protocol, including 44 institutionalized children randomly assigned to receive care as usual, 41 institutionalized children randomized to be removed from institutional care and placed in high-quality foster care in infancy, and a control group of 42 demographically matched children raised in biological families. Outcomes included body mass index (BMI), systolic and diastolic blood pressure, C-reactive protein, interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor α, glycosylated hemoglobin A1c, and Epstein-Barr virus antibody titers. Early institutional rearing was not associated with differences in cardiometabolic or immune markers. Randomization to foster care and age of placement into foster care were also unrelated to these markers, with the exception of BMI z-score, where children assigned to care as usual had lower BMI z-scores relative to children assigned to foster care (-0.23 versus 0.08, p = .06), and older age at placement was associated with lower BMI (β = -0.07, p = .03). The impact of institutional rearing on measures of cardiometabolic health and immune system functioning is either absent or not evident until later in development. These findings provide new insights into the biological embedding of adversity and how it varies developmentally and across regulatory systems and adversity type. NCT00747396.

Assessing the Foundational Studies on Adverse Childhood Experiences

This article critically reviews the foundational studies carried out by Felitti in the US and Bellis in the UK and their colleagues examining the relationship between Adverse Childhood Experiences (ACEs) and adult health and morbidity. These studies have paved the way for much research on childhood adversity and its impact on child development and brain functioning at a family level. ACEs have gained traction in the UK in terms of policy targeting dysfunctional families through early intervention to stop the intergenerational effects of adverse childhood experiences. This article questions the foundational research that argues for family-level, parent-based intervention, especially in light of substantial evidence about the biological embedding of poverty and the direct links between disadvantage and child development. It also hopes to raise awareness about the contested nature of ACEs and their growing influence on family policy.

Establishing a generalized polyepigenetic biomarker for tobacco smoking

Large-scale epigenome-wide association meta-analyses have identified multiple ‘signatures’’ of smoking. Drawing on these findings, we describe the construction of a polyepigenetic DNA methylation score that indexes smoking behavior and that can be utilized for multiple purposes in population health research. To validate the score, we use data from two birth cohort studies: The Dunedin Longitudinal Study, followed to age-38 years, and the Environmental Risk Study, followed to age-18 years. Longitudinal data show that changes in DNA methylation accumulate with increased exposure to tobacco smoking and attenuate with quitting. Data from twins discordant for smoking behavior show that smoking influences DNA methylation independently of genetic and environmental risk factors. Physiological data show that changes in DNA methylation track smoking-related changes in lung function and gum health over time. Moreover, DNA methylation changes predict corresponding changes in gene expression in pathways related to inflammation, immune response, and cellular trafficking. Finally, we present prospective data about the link between adverse childhood experiences (ACEs) and epigenetic modifications; these findings document the importance of controlling for smoking-related DNA methylation changes when studying biological embedding of stress in life-course research. We introduce the polyepigenetic DNA methylation score as a tool both for discovery and theory-guided research in epigenetic epidemiology.

The Interpersonal Neurobiology of Child Maltreatment: Parasympathetic Substrates of Interactive Repair in Maltreating and Nonmaltreating Mother-Child Dyads.

Children's repair of conflict with parents may be particularly challenging in maltreating families, and early, stressful parent-child interactions may contribute to children's altered neurobiological regulatory systems. To explore neurobiological signatures of repair processes, we examined whether mother and child individual and dyadic respiratory sinus arrhythmia (RSA) covaried with interactive repair differently in maltreating versus nonmaltreating mother-preschooler dyads (N = 101), accounting for whether repair was mother or child initiated. Mother-initiated repair was equally frequent and protective across groups, associated with no change in mother or child RSA at higher levels of repair. But lower levels of mother repair were associated with child RSA withdrawal in nonmaltreating dyads versus child RSA augmentation in maltreating dyads. In maltreating dyads only, higher child-initiated repair was associated with higher mean mother RSA, whereas lower child repair was associated with mother RSA withdrawal. Findings suggest that interactive repair may have a buffering effect on neurobiological regulation but also that maltreating mothers and children show atypical neurobiological response to interpersonal challenges including differences related to children conducting the work of interactive repair that maltreating parents are less able to provide. We conclude by considering the role of maladaptive parent-child relationship processes in the biological embedding of early adversity.

Socioeconomic position during pregnancy and DNA methylation signatures at three stages across early life: epigenome-wide association studies in the ALSPAC birth cohort.

BackgroundSocioeconomic experiences are recognized determinants of health, and recent work has shown that social disadvantages in early life may induce sustained biological changes at molecular level that are detectable later in life. However, the dynamics and persistence of biological embedding of socioeconomic position (SEP) remains vastly unexplored.MethodsUsing the data from the ALSPAC birth cohort, we performed epigenome-wide association studies of DNA methylation changes at three life stages (birth, n = 914; childhood at mean age 7.5 years, n = 973; and adolescence at mean age 15.5 years, n = 974), measured using the Illumina HumanMethylation450 Beadchip, in relation to pregnancy SEP indicators (maternal and paternal education and occupation).ResultsAcross the four early life SEP metrics investigated, only maternal education was associated with methylation levels at birth, and four CpGs mapped to SULF1, GLB1L2 and RPUSD1 genes were identified [false discovery rate (FDR)-corrected P-value <0.05]. No epigenetic signature was found associated with maternal education in child samples, but methylation levels at 20 CpG loci were found significantly associated with maternal education in adolescence. Although no overlap was found between the differentially methylated CpG sites at different ages, we identified two CpG sites at birth and during adolescence which are 219 bp apart in the SULF1 gene that encodes an heparan sulphatase involved in modulation of signalling pathways. Using data from an independent birth cohort, the ENVIRONAGE cohort, we were not able to replicate these findings.ConclusionsTaken together, our results suggest that parental SEP, and particularly maternal education, may influence the offspring’s methylome at birth and adolescence.

The biological embedding of neonatal stress exposure: A conceptual model describing the mechanisms of stress-induced neurodevelopmental impairment in preterm infants.

The biological embedding of early life stress exposure may result in life-long neurodevelopmental impairment in preterm infants. Infants hospitalized in the neonatal intensive care unit are exposed to significant experiential, environmental, and physiologic stressors over the course of their extended hospitalization. Stress exposure during the sensitive period of brain development may alter biological processes, including functioning of the immune system, the autonomic nervous system, and the hypothalamic-pituitary-adrenal axis as well as gene expression. These alterations may subsequently affect brain structure and function. Changes to these processes may mediate the relationship between neonatal stress exposure and neurodevelopment in preterm infants and represent potential therapeutic targets to improve long-term outcomes. The purpose of this paper is to introduce a conceptual model, based on published research, that describes the mechanisms mediating stress exposure and neurodevelopment impairment in preterm infants and to provide the theoretical foundation on which to base future descriptive research, intervention studies, and clinical care.

The biological embedding of early-life socioeconomic status and family adversity in children's genome-wide DNA methylation.

Aim:To examine variation in child DNA methylation to assess its potential as a pathway for effects of childhood social adversity on health across the life course.Materials & methods:In a diverse, prospective community sample of 178 kindergarten children, associations between three types of social experience and DNA methylation within buccal epithelial cells later in childhood were examined.Results:Family income, parental education and family psychosocial adversity each associated with increased or decreased DNA methylation (488, 354 and 102 sites, respectively) within a unique set of genomic CpG sites. Gene ontology analyses pointed to genes serving immune and developmental regulation functions.Conclusion:Findings provided support for DNA methylation as a biomarker linking early-life social experiences with later life health in humans.

Michelle E. Deming: commentary on Gender-Based violence and trauma in marginalized populations of women: Role of biological embedding and toxic stress

Authors that address gender based violence (GBV) using interdisciplinary frameworks integrating multiple perspectives are fraught with challenges. Sabri and Granger (2018) show that integrating the...

Thinking Across Generations: Unique Contributions of Maternal Early Life and Prenatal Stress to Infant Physiology

Respiratory sinus arrhythmia (RSA) is a parasympathetic-mediated biomarker of self-regulation linked to lifespan mental and physical health outcomes. Intergenerational impacts of mothers’ exposure to prenatal stress have been demonstrated, but evidence for biological embedding of maternal preconception stress, including adverse childhood experiences (ACEs), on infant RSA is lacking. We examine the independent effects of maternal ACEs and prenatal stress on infant RSA, seeking to broaden the understanding of the earliest origins of mental and physical health risks.

Honey bee neurogenomic responses to affiliative and agonistic social interactions.

Social interactions can be divided into two categories, affiliative and agonistic. How neurogenomic responses reflect these opposing valences is a central question in the biological embedding of experience. To address this question, we exposed honey bees to a queen larva, which evokes nursing, an affiliative alloparenting interaction, and measured the transcriptomic response of the mushroom body brain region at different times after exposure. Hundreds of genes were differentially expressed at distinct time points, revealing a dynamic temporal patterning of the response. Comparing these results to our previously published research on agonistic aggressive interactions, we found both shared and unique transcriptomic responses to each interaction. The commonly responding gene set was enriched for nuclear receptor signaling, the set specific to nursing was enriched for olfaction and neuron differentiation, and the set enriched for aggression was enriched for cytoskeleton, metabolism, and chromosome organization. Whole brain histone profiling after the affiliative interaction revealed few changes in chromatin accessibility, suggesting that the transcriptomic changes derive from already accessible areas of the genome. Although only one stimulus of each type was studied, we suggest that elements of the observed transcriptomic responses reflect molecular encoding of stimulus valence, thus priming individuals for future encounters. This hypothesis is supported by behavioral analyses showing that bees responding to either the affiliative or agonistic stimulus exhibited a higher probability of repeating the same behavior but a lower probability of performing the opposite behavior. These findings add to our understanding of the biological embedding at the molecular level.

Gender-based violence and trauma in marginalized populations of women: Role of biological embedding and toxic stress

Gender-based violence (GBV) and trauma can dysregulate and recalibrate environmentally sensitive physiological (i.e. central nervous, endocrine, and immune) systems placing survivors at risk for multiple health problems. The researchers build the case that the effects of GBV are likely to be particularly high impact and contribute to health disparities for marginalized survivors of GBV. Further, the researchers underscore a need for a multi-level bio-socio-ecological model that deciphers, characterizes, and explains individual differences in these effects and the need to establish an evidence base from which to derive interventions that address biological effects of toxic stress among marginalized survivors of GBV.

Biological embedding of neighborhood disadvantage and collective efficacy: Influences on chronic illness via accelerated cardiometabolic age.

The present study extends prior research on the link between neighborhood disadvantage and chronic illness by testing an integrated model in which neighborhood characteristics exert effects on health conditions through accelerated cardiometabolic aging. Hypotheses were tested using a sample of 408 African Americans from the Family and Community Health Study. Using four waves of data spanning young adulthood (ages 18-29), we first found durable effects of neighborhood disadvantage on accelerated cardiometabolic aging and chronic illness. Then, we used marginal structural modeling to adjust for potential neighborhood selection effects. As expected, accelerated cardiometabolic aging was the biopsychosocial mechanism that mediated much of the association between neighborhood disadvantage and chronic illness. This finding provides additional support for the view that neighborhood disadvantage can influence morbidity and mortality by creating social contexts that becomes biologically embedded. Perceived neighborhood collective efficacy served to buffer the relationship between neighborhood disadvantage and biological aging, identifying neighborhood-level resilience factor. Overall, our results indicate that neighborhood context serves as a fundamental cause of weathering and accelerated biological aging. Residing in a disadvantaged neighborhood increases biological wear and tear that ultimately leads to onset of chronic illness, but access to perceived collective efficacy buffers the impact of these neighborhood effects. From an intervention standpoint, identifying such an integrated model may help inform future health-promoting interventions.

Social environment, biological embedding and social inequalities in health

The social gradient in health refers to the fact that the higher individuals rise in the social hierarchy, the better is their health. Understanding the construction of this gradient is a major challenge in social epidemiology. An original approach consists in looking at how the different exposures (chemical, physical, behavioural, psychosocial…) associated with the social environment are ultimately expressed at the biological level influencing health positively or negatively, referring to the concept of biological embedding. Data from animal models and life course epidemiology have shed new light on the biological mechanisms potentially at play. Recent discoveries from the field of epigenetics provide a better understanding of how the social environment, especially the early environment, can influence biological functioning over the long term or even over several generations. The work on the biological embedding of the social environment in connection with epigenetics still needs to be very largely consolidated, but could constitute a change of perspective in human biology, particularly by reconsidering the influence of the environment on biological functioning, which is not without consequences in terms of public health interventions.

19. Hazards to Early Development: The Biological Embedding of Early Life Adversity

The number of children under 18 years has increased worldwide over the past decade. This growth spurt is due, in part, to remarkable progress in child survival. Alas, surviving early hazards like prematurity or infectious disease does not guarantee that children’s development will not be compromised by other hazards as they grow older. Throughout the world, children continue to be confronted with a large number of biological and psychosocial challenges that greatly limit their developmental potential.

16.1 EPIGENETIC SIGNATURES OF CHILDHOOD AND ADOLESCENT VICTIMISATION USING A GENETICALLY SENSITIVE LONGITUDINAL COHORT STUDY.

BackgroundStress is a normal, adaptive response to stressors (e.g. events that make a person feel threatened or upset). However, healthy development can be derailed by excessive or prolonged exposure to stress especially during important developmental periods such as childhood and adolescence. Exposure to severe stress may have immediate as well as long-lasting damaging effects on learning, behaviour, and health, and has been implicated in the development of psychosis. One way these may occur is via changes to epigenetic processes (e.g. alterations in DNA methylation). Initial studies have shown that individuals exposed to severe psychosocial stress have different patterns of DNA methylation (epigenetic ‘signatures’) compared to individuals exposed to no/minimal stressful life events, but these studies are methodologically limited.MethodsThis paper describes our examination of the potential link between exposure to multiple forms of severe victimisation (poly-victimisation) during childhood adolescence and DNA methylation differences utilising data from the Environmental Risk (E-Risk) Longitudinal Twin Study, an epidemiological study of 2,232 children (1,116 twin pairs) born in 1994–1995 in England and Wales and followed to 18 years of age (with 93% retention). Multiple forms of victimisation were ascertained in childhood and adolescence (including physical, sexual and emotional abuse, neglect, exposure to intimate-partner violence, bullying, cyber- and crime victimization) by combining the best practices in survey research with comprehensive interview-based approaches. Whole blood samples were collected from participants at age 18, and the extracted DNA was used to quantify genome-wide patterns of DNA methylation.ResultsEpigenome-wide analyses of poly-victimisation across childhood and adolescence revealed several significant associations with DNA methylation in peripheral blood at age 18 years, but these were confounded by tobacco smoking and/or did not survive co-twin control tests. Secondary analyses of specific forms of victimisation revealed sparse associations with DNA methylation that did not replicate across different operationalisations of the same putative victimization experience. Hypothesis-driven analyses of six candidate genes in the stress response (NR3C1, FKBP5, BDNF, AVP, CRHR1, SLC6A4) did not reveal predicted associations with DNA methylation in probes annotated to these genes.DiscussionFindings from this epidemiological analysis of the epigenetic effects of early-life stress do not support the hypothesis of robust changes in DNA methylation in victimised young people. It is possible that epigenetic epidemiology is not yet well matched to experimental, non-human models in uncovering the biological embedding of stress.

Commentary: Biological embedding of childhood adversity: where do we go from here? A reflection on Koss and Gunnar (2018).

The review by Koss & Gunna provides a scholarly overview of the role of the hypothalamic-pituitary-adrenal (HPA) axis in mediating the association between childhood adversity and psychopathology. Through their insightful observations, the authors craft a rich framework to critically appraise the current evidence and inform future research in this area. Overall, the review calls for a new generation of studies testing biological embedding hypotheses with greater attention to design, measurement, statistical models, and translational approaches. These new studies are much needed. By uncovering the causal pathways underlying the biological embedding of childhood adversity, we can gain important new tools to prevent the most impairing forms of psychopathology among the most vulnerable individuals in society.

Psychological Stress and Mitochondria: A Conceptual Framework.

The integration of biological, psychological, and social factors in medicine has benefited from increasingly precise stress response biomarkers. Mitochondria, a subcellular organelle with its own genome, produce the energy required for life and generate signals that enable stress adaptation. An emerging concept proposes that mitochondria sense, integrate, and transduce psychosocial and behavioral factors into cellular and molecular modifications. Mitochondrial signaling might in turn contribute to the biological embedding of psychological states. A narrative literature review was conducted to evaluate evidence supporting this model implicating mitochondria in the stress response, and its implementation in behavioral and psychosomatic medicine. Chronically, psychological stress induces metabolic and neuroendocrine mediators that cause structural and functional recalibrations of mitochondria, which constitutes mitochondrial allostatic load. Clinically, primary mitochondrial defects affect the brain, the endocrine system, and the immune systems that play a role in psychosomatic processes, suggesting a shared underlying mechanistic basis. Mitochondrial function and dysfunction also contribute to systemic physiological regulation through the release of mitokines and other metabolites. At the cellular level, mitochondrial signaling influences gene expression and epigenetic modifications, and modulates the rate of cellular aging. This evidence suggests that mitochondrial allostatic load represents a potential subcellular mechanism for transducing psychosocial experiences and the resulting emotional responses-both adverse and positive-into clinically meaningful biological and physiological changes. The associated article in this issue of Psychosomatic Medicine presents a systematic review of the effects of psychological stress on mitochondria. Integrating mitochondria into biobehavioral and psychosomatic research opens new possibilities to investigate how psychosocial factors influence human health and well-being across the life-span.

Dynamics of body time, social time and life history at adolescence

Recent opposing trends towards earlier physical maturation and later social maturation present a conundrum of apparent biological-social mismatch. Here we use life history analysis from evolutionary ecology to identify forces that drive these shifts. Together with findings in developmental science, our life history analysis indicates that adolescence is a distinctive period for biological embedding of culture. Ethnographic evidence shows that mass education is a novel feature of the globalizing cultural configurations of adolescence, which are driven by transformations in labour, livelihood and lifestyle. Evaluation of the life history trade-offs and sociocultural ecologies that are experienced by adolescents may offer a practical basis for enhancing their development.

Analysis of DNA Methylation in Young People: Limited Evidence for an Association Between Victimization Stress and Epigenetic Variation in Blood.

DNA methylation has been proposed as an epigenetic mechanism by which early-life experiences become "embedded" in the genome and alter transcriptional processes to compromise health. The authors sought to investigate whether early-life victimization stress is associated with genome-wide DNA methylation. The authors tested the hypothesis that victimization is associated with DNA methylation in the Environmental Risk (E-Risk) Longitudinal Study, a nationally representative 1994-1995 birth cohort of 2,232 twins born in England and Wales and assessed at ages 5, 7, 10, 12, and 18 years. Multiple forms of victimization were ascertained in childhood and adolescence (including physical, sexual, and emotional abuse; neglect; exposure to intimate-partner violence; bullying; cyber-victimization; and crime). Epigenome-wide analyses of polyvictimization across childhood and adolescence revealed few significant associations with DNA methylation in peripheral blood at age 18, but these analyses were confounded by tobacco smoking and/or did not survive co-twin control tests. Secondary analyses of specific forms of victimization revealed sparse associations with DNA methylation that did not replicate across different operationalizations of the same putative victimization experience. Hypothesis-driven analyses of six candidate genes in the stress response (NR3C1, FKBP5, BDNF, AVP, CRHR1, SLC6A4) did not reveal predicted associations with DNA methylation in probes annotated to these genes. Findings from this epidemiological analysis of the epigenetic effects of early-life stress do not support the hypothesis of robust changes in DNA methylation in victimized young people. We need to come to terms with the possibility that epigenetic epidemiology is not yet well matched to experimental, nonhuman models in uncovering the biological embedding of stress.