The biological embedding of social adversity: How adolescent housing insecurity impacts inflammation over time.

BACKGROUND & PURPOSE: Adolescent housing insecurity is a dynamic form of social adversity that impacts child health outcomes worldwide. However, the means by which adolescent housing insecurity may become biologically embedded to influence health outcomes over the life course remain unclear. Therefore, we aimed to utilize life course perspectives and advanced causal inference methods to evaluate the potential for inflammation to contribute to the biological embedding of adolescent housing insecurity. MATERIALS AND METHODS: Using prospective data from the Great Smoky Mountains Study, we investigated the relationship between adolescent housing insecurity and whole-blood spot samples assayed for C-reactive protein (CRP). Adolescent housing insecurity was created based on annual measures of frequent residential moves, reduced standard of living, forced separation from the home, and foster care. Annual measures of CRP ranged from 0.001 mg/L to 13.6 mg/L (median = 0.427 mg/L) and were log10 transformed to account for positively skewed values. We used g-estimation of structural nested mean models to estimate a series of conditional average causal effects of adolescent housing insecurity on CRP levels from ages 11 to 16 years and interpreted the results within life course frameworks of accumulation, recency, and sensitive periods. PRINCIPAL RESULTS: Of the 1,334 participants, 427 [44.3 %] were female. Based on the conditional average causal effect, one exposure to adolescent housing insecurity from ages 11 to 16 years led to a 6.4 % (95 % CI = 0.69 - 12.4) increase in later CRP levels. Exposure at 14 years of age led to a 27.9 % increase in CRP levels at age 15 (95 % CI = 6.5 - 53.5). Recent exposures to adolescent housing insecurity (<3 years) suggested stronger associations with CRP levels than distant exposures (>3 years), but limited statistical power prevented causal conclusions regarding recency effects at the risk of a Type II Error. MAJOR CONCLUSIONS: These findings highlight inflammation-as indicated by increased CRP levels-as one potential mechanism for the biological embedding of adolescent housing insecurity. The results also suggest that adolescent housing insecurity-particularly recent, repeated, and mid-adolescent exposures-may increase the risk of poor health outcomes and should be considered a key intervention target.

DNA methylation signatures of early-life adversity are exposure-dependent in wild baboons.

The early-life environment can profoundly shape the trajectory of an animal's life, even years or decades later. One mechanism proposed to contribute to these early-life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early-life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early-life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early-life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early-life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early-life effects on fitness-related traits.

Linking environmental factors and gene regulation.

A technique called mSTARR-seq sheds light on how DNA methylation may shape responses to external stimuli by altering the activity of sequences that control gene expression.

DNA methylation-environment interactions in the human genome.

Previously, we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al., 2018). Here, we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures-one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance.

Exposure to parental depression in adolescence and proinflammatory phenotypes 20 years later.

Although the biological embedding model of adversity proposes that stressful experiences in childhood create a durable proinflammatory phenotype in immune cells, research to date has relied on study designs that limit our ability to make conclusions about whether the phenotype is long-lasting. The present study leverages an ongoing 20-year investigation of African American youth to test research questions about the extent to which stressors measured in childhood forecast a proinflammatory phenotype in adulthood, as indicated by exaggerated cytokine responses to bacterial stimuli, monocyte insensitivity to inhibitory signals from hydrocortisone, and low-grade inflammation. Parents reported on their depressive symptoms and unsupportive parenting tendencies across youths' adolescence. At age 31, youth participants (now adults) completed a fasting blood draw. Samples were incubated with lipopolysaccharide and doses of hydrocortisone to evaluate proinflammatory processes. Additionally, blood samples were tested for indicators of low-grade inflammation, including IL-6, IL-8, IL-10, and TNF-α, and soluble urokinase plasminogen activator receptor. Analyses revealed that parental depression across youths' adolescence prospectively predicted indicators of proinflammatory phenotypes at age 31. Follow-up analyses suggested that unsupportive parenting mediated these associations. These findings suggest that exposure to parental depression in adolescence leaves an imprint on inflammatory activity that can be observed 20 years later.

[Emotional Abuse in Childhood and Adolescence: Biological Embedding and Clinical Implications]. / Emotionaler Missbrauch in Kindheit und Jugend ­ Biologische Einbettung und klinische Implikationen.

Emotional abuse, defined as degrading, manipulative, or neglectful behaviors by caregivers, represents a common adverse experience for children and adolescents, often co-occurring with other maltreatment types. Exposure to emotional abuse significantly affects mental health across the lifespan and is particularly associated with elevated depression risk.This review examinesmechanisms, by which emotional abuse influences brain development and the neuroendocrine stress response system and discusses the roles of genetic vulnerability and epigenetic processes in contributing to an elevated mental health risk. Emotional abuse has similar effects on brain networks responsible for emotion processing and regulation as other maltreatment types.Moreover, it uniquely affects networks related to self-relevant information and socio-cognitive processes. Furthermore, emotional abuse is associated with an impaired recovery of the neuroendocrine response to acute stress. Similar to other maltreatment types, emotional abuse is associated with epigenetic changes in genes regulating the neuroendocrine stress response system that are implicated in increased mental health risk.These findings suggest that emotional abuse has equally detrimental effects on children'smental health as physical or sexual abuse, warranting broader societal awareness and enhanced early detection efforts. Early interventions should prioritize emotion regulation, social cognition, self-esteemenhancement, and relationship- oriented approaches for victims of emotional abuse.

Social determinants of health and obstetric outcomes: A report and recommendations of the workshop of the Society for Maternal-Fetal Medicine.

This article is a report of a 2-day workshop, entitled "Social determinants of health and obstetric outcomes," held during the Society for Maternal-Fetal Medicine 2022 Annual Pregnancy Meeting. Participants' fields of expertise included obstetrics, pediatrics, epidemiology, health services, health equity, community-based research, and systems biology. The Commonwealth Foundation and the Alliance of Innovation on Maternal Health cosponsored the workshop and the Society for Women's Health Research provided additional support. The workshop included presentations and small group discussions, and its goals were to accomplish the following.

Association between adverse childhood experiences and later-life allostatic load in UK Biobank female participants.

BACKGROUND: Adverse childhood experiences during key developmental periods have been shown to impact long-term health outcomes. Adverse childhood experiences may include psychological, physical, or sexual abuse; neglect; or socioeconomic factors. Adverse childhood experiences are linked with an increase in poor health behavior such as smoking and alcohol consumption, and may also influence epigenetic changes, inflammatory response, metabolic changes, and allostatic load. OBJECTIVE: We sought to explore associations between adverse childhood experiences and allostatic load in adult female participants in the UK Biobank. DESIGN: The UK Biobank is a multisite cohort study established to capture lifestyle, environment, exposure, health history, and genotype data on individuals in the United Kingdom. METHODS: Adverse childhood experiences were assessed from the Childhood Trauma Screener, which measures abuse and neglect across five items. Biological measures at enrollment were used to construct allostatic load, including measures of metabolic, inflammatory, and cardiovascular function. Females with a cancer diagnosis prior to enrollment were removed as it may influence allostatic load. Poisson regression models were used to assess the association between adverse childhood experiences and allostatic load, accounting for a priori confounders. RESULTS: A total of 33,466 females with complete data were analyzed, with a median age at enrollment of 54 (range = 40-70) years. Among the study sample, the mean allostatic load ranged from 1.85 in those who reported no adverse childhood experiences to 2.45 in those with all adverse childhood experiences reported. In multivariable analysis, there was a 4% increase in average allostatic load among females for every additional adverse childhood experience reported (incidence rate ratio = 1.04, 95% confidence interval = 1.03-1.05). Similar results were observed when assessing individual adverse childhood experience components. CONCLUSION: This analysis supports a growing body of evidence suggesting that increased exposure to early life abuse or neglect is associated with increased allostatic load in females.

Biological embedding vs. embodiment of social experiences: How these two concepts form distinct thought styles around the social production of health inequalities.

OBJECTIVES: This article compares research on biological embedding and the embodiment of social experiences, two concepts proposed in the 1990s to introduce a new perspective on the social production of health inequalities. We draw on Ludwig Fleck's concept of 'thought style' (1935/2008) to question the possible emergence of a common research program around the processes by which the social becomes biological. METHODS: We compiled a corpus of 322 articles referring to either biological embedding or to the embodiment of social experiences, identified in the Web of Science core collection and published from 1990 to 2021. We analyzed the articles' use of these concepts using scientometric indicators and qualitative content analysis. RESULTS: Initial differences between the research agendas associated with biological embedding and embodiment are strengthened as both concepts circulate around scientific communities studying the social production of health inequalities. Thought styles formed around embedding and embodiment differ significantly in terms of shared references, sets of methods and research questions, and policy recommendations. Research on biological embedding forms a thought style shared by researchers in the biomedical and public health sciences. Conversely, the concept of embodiment of social experiences connects perspectives from biomedical, public health, human and social sciences, and gathers three thought styles, one identical to that of biological embedding and two formed in social epidemiology and in medical anthropology. CONCLUSIONS: Acknowledging the differences between the concepts and divergences in their evolution provides an opportunity for identification of topics where thought styles are either complementary or in tension.

Childhood Trauma and Epigenetics: State of the Science and Future.

PURPOSE OF REVIEW: There is a great deal of interest regarding the biological embedding of childhood trauma and social exposures through epigenetic mechanisms, including DNA methylation (DNAm), but a comprehensive understanding has been hindered by issues of limited reproducibility between studies. This review presents a summary of the literature on childhood trauma and DNAm, highlights issues in the field, and proposes some potential solutions. RECENT FINDINGS: Investigations of the associations between DNAm and childhood trauma are commonly performed using candidate gene approaches, specifically involving genes related to neurological and stress pathways. Childhood trauma is defined in a wide range of ways in several societal contexts. However, although variations in DNAm are frequently found in stress-related genes, unsupervised epigenome-wide association studies (EWAS) have shown limited reproducibility both between studies and in relating these changes to exposures. The reproducibility of childhood trauma DNAm studies, and the field of social epigenetics in general, may be improved by increasing sample sizes, standardizing variables, making use of effect size thresholds, collecting longitudinal and intervention samples, appropriately accounting for known confounding factors, and applying causal analysis wherever possible, such as "two-step epigenetic Mendelian randomization."

The mediating role of allostatic load in the relationship between early life adversity and cognitive function across the adult lifespan.

Early life adversity is consequential for poor cognitive health in mid to late-life. Early life adversity is associated with higher allostatic load, a biological indicator of physiological dysregulation due to cumulative wear-and-tear from chronic stress. Higher allostatic load is also associated with poorer cognitive function across the lifespan. To date, a paucity of research has examined allostatic load as a mechanism through which early life adversity impacts cognition in adulthood. Using cross-sectional data from the Midlife in the United States (MIDUS) Study, the objective of the current study was to investigate the mediating role of allostatic load in the relationship between early life adversity and cognitive performance (global cognition, episodic memory, executive function) among middle-aged and older adults without cognitive impairment (n = 1541, Mage=53 ± 12, 53% female). Early life adversity was measured retrospectively using the Childhood Trauma Questionnaire. Allostatic load was composed of 20 biomarker proxies of neuroendocrine, metabolic, inflammatory, and cardiovascular systems, stratified by sex. Cognitive performance was evaluated using a battery of standardized neuropsychological tests. Controlling for age, education, and race, allostatic load significantly mediated the relationship between early life adversity and global cognition (ß=-0.01, 95%CI [-0.01,-0.001]), and early life adversity and executive function (ß=-0.01, 95%CI [-0.01,-0.001]), but not episodic memory. Findings did not change after controlling for lifestyle behaviours and current depression. Consistent with the biopsychosocial lifespan model of cognitive aging, findings suggest that early life adversity may become biologically embedded over time to negatively impact cognitive function in later adulthood in a domain-specific manner.

Context-dependent influence of threat on honey bee social network dynamics and brain gene expression.

Adverse social experience affects social structure by modifying the behavior of individuals, but the relationship between an individual's behavioral state and its response to adversity is poorly understood. We leveraged naturally occurring division of labor in honey bees and studied the biological embedding of environmental threat using laboratory assays and automated behavioral tracking of whole colonies. Guard bees showed low intrinsic levels of sociability compared with foragers and nurse bees, but large increases in sociability following exposure to a threat. Threat experience also modified the expression of caregiving-related genes in a brain region called the mushroom bodies. These results demonstrate that the biological embedding of environmental experience depends on an individual's societal role and, in turn, affects its future sociability.

Maternal Prenatal Anxiety and the Fetal Origins of Epigenetic Aging.

BACKGROUND: The fetal origins of mental health is a well-established framework that currently lacks a robust index of the biological embedding of prenatal adversity. The Pediatric-Buccal-Epigenetic (PedBE) clock is a novel epigenetic tool that associates with aspects of the prenatal environment, but additional validation in longitudinal datasets is required. Likewise, the relationship between prenatal maternal mental health and the PedBE clock has not been described. METHODS: Longitudinal cohorts from the Netherlands (Basal Influences on Baby Development [BIBO] n = 165) and Singapore (Growing Up in Singapore Towards Healthy Outcomes [GUSTO] n = 340) provided data on prenatal maternal anxiety and longitudinal assessments of buccal cell-derived genome-wide DNA methylation assessed at 6 and 10 years of age in BIBO, and at 3, 9, and 48 months of age in GUSTO. Measures of epigenetic age acceleration were calculated using the PedBE clock and benchmarked against an established multi-tissue epigenetic predictor. RESULTS: Prenatal maternal anxiety predicted child PedBE epigenetic age acceleration in both cohorts, with effects largely restricted to males and not females. These results were independent of obstetric, socioeconomic, and genetic risk factors, with a larger effect size for prenatal anxiety than depression. PedBE age acceleration predicted increased externalizing symptoms in males from mid- to late childhood in the BIBO cohort only. CONCLUSIONS: These findings point to the fetal origins of epigenetic age acceleration and reveal an increased sensitivity in males. Convergent evidence underscores the societal importance of providing timely and effective mental health support to pregnant individuals, which may have lasting consequences for both mother and child.

Limitations of the protective measure theory in explaining the role of childhood sexual abuse in eating disorders, addictions, and obesity: an updated model with emphasis on biological embedding.

In addition to its immediate negative consequences, childhood sexual abuse is associated with lifelong deleterious mental and physical health outcomes. This review employs a biopsychosocial perspective to better understand pathways from childhood sexual abuse to eating disorders, food and drug addictions, and obesity across the life course. Guided by an updated conceptual model, this review delineates how the biological embedding of childhood sexual abuse triggers a cascade of interrelated conditions that often result in failed attempts at weight suppression and eventually obesity. Such biological embedding involves pathways such as inflammation, allostatic load, reward sensitivity, activation of the hypothalamic-pituitary-adrenal axis, epigenetics, and structural and functional changes in the brain. These pathways are in turn theorized to lead to food addiction, substance use disorder, and eating disorders-each with potential pathways toward obesity over time. Predisposing factors to childhood sexual abuse including gender, culture, and age are discussed. This model calls into question the longstanding "protective measure" theory that purports individuals exposed to sexual abuse will deliberately or subconsciously gain weight in attempt to prevent future victimization. A more comprehensive understanding of the mechanisms by which childhood sexual abuse becomes biologically embedded may help clinicians and survivors normalize and/or address disordered eating and weight-related outcomes, as well as identify intervention strategies.Level of evidence: Level V: opinions of respected authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

Re(Setting) Epigenetic Clocks: An Important Avenue Whereby Social Conditions Become Biologically Embedded across the Life Course.

Research on biological embedding of the social environment has been expedited by increased availability of biomarkers. Recently, this arsenal of measures has been expanded to include epigenetic clocks that indicate in years the extent to which an individual is older or younger than their chronological age. These measures of biological aging, especially GrimAge, are robust predictors of both illness and time to death. Importantly for sociologists, several studies have linked social conditions to these indices of aging. The present study extends this research using longitudinal data from a sample of 223 black women participating in the Family and Community Health Study. We find that changes in income and living arrangements over an 11-year period predict changes in speed of biological aging. These results provide further support for the idea that epigenetic aging is a mechanism whereby social conditions become biologically embedded. The utility of epigenetic clocks for sociological studies of health are discussed.

Neural and Molecular Mechanisms of Biological Embedding of Social Interactions.

Animals operate in complex environments, and salient social information is encoded in the nervous system and then processed to initiate adaptive behavior. This encoding involves biological embedding, the process by which social experience affects the brain to influence future behavior. Biological embedding is an important conceptual framework for understanding social decision-making in the brain, as it encompasses multiple levels of organization that regulate how information is encoded and used to modify behavior. The framework we emphasize here is that social stimuli provoke short-term changes in neural activity that lead to changes in gene expression on longer timescales. This process, simplified-neurons are for today and genes are for tomorrow-enables the assessment of the valence of a social interaction, an appropriate and rapid response, and subsequent modification of neural circuitry to change future behavioral inclinations in anticipation of environmental changes. We review recent research on the neural and molecular basis of biological embedding in the context of social interactions, with a special focus on the honeybee.

Early maternal loss leads to short- but not long-term effects on diurnal cortisol slopes in wild chimpanzees.

The biological embedding model (BEM) suggests that fitness costs of maternal loss arise when early-life experience embeds long-term alterations to hypothalamic-pituitary-adrenal (HPA) axis activity. Alternatively, the adaptive calibration model (ACM) regards physiological changes during ontogeny as short-term adaptations. Both models have been tested in humans but rarely in wild, long-lived animals. We assessed whether, as in humans, maternal loss had short- and long-term impacts on orphan wild chimpanzee urinary cortisol levels and diurnal urinary cortisol slopes, both indicative of HPA axis functioning. Immature chimpanzees recently orphaned and/or orphaned early in life had diurnal cortisol slopes reflecting heightened activation of the HPA axis. However, these effects appeared short-term, with no consistent differences between orphan and non-orphan cortisol profiles in mature males, suggesting stronger support for the ACM than the BEM in wild chimpanzees. Compensatory mechanisms, such as adoption, may buffer against certain physiological effects of maternal loss in this species.

Assembling a cohort for in-depth, longitudinal assessments of the biological embedding of child maltreatment: Methods, complexities, and lessons learned.

As championed by the work of Ed Zigler, investing in nurturing environments for all children is a chief tenet of primary prevention that will have far-reaching benefits to the health and welfare of all members of society. Children who endure child maltreatment (CM) are among society's most vulnerable. Prospective longitudinal research aimed at a comprehensive understanding of the mechanisms linking CM to subsequent adverse health consequences is needed to improve outcomes and to strengthen causal inference. This paper outlines the methods of the Child Health Study (CHS), a large, state-wide longitudinal cohort of recently maltreated and nonmaltreated youth aged 8-13 who will be assessed every 2 years. The CHS is designed to include in-depth assessments of multiple environmental, behavioral, neural, physiological, and molecular mechanisms through which CM may impact a broad spectrum of youth development, including behavioral and physical health outcomes. In addition to describing the conceptual framework and methods underlying the CHS, we provide information on valuable "lessons learned" in the hopes of supporting future research efforts facing similar challenges. The ultimate goal of this research is demonstrating how policies regarding CM impact the well-being, resilience and recovery of survivors and that they are worthy of large public investment.

Associations between childhood family emotional health, fronto-limbic grey matter volume, and saliva 5mC in young adulthood.

BACKGROUND: Poor family emotional health (FEH) during childhood is prevalent and impactful, and likely confers similar neurodevelopmental risks as other adverse social environments. Pointed FEH study efforts are underdeveloped, and the mechanisms by which poor FEH are biologically embedded are unclear. The current exploratory study examined whether variability in 5-methyl-cytosine (5mC) and fronto-limbic grey matter volume may represent pathways through which FEH may become biologically embedded. RESULTS: In 98 university students aged 18-22 years, retrospective self-reported childhood FEH was associated with right hemisphere hippocampus (b = 10.4, p = 0.005), left hemisphere amygdala (b = 5.3, p = 0.009), and right hemisphere amygdala (b = 5.8, p = 0.016) volumes. After pre-processing and filtering to 5mC probes correlated between saliva and brain, analyses showed that childhood FEH was associated with 49 5mC principal components (module eigengenes; MEs) (prange = 3 × 10-6 to 0.047). Saliva-derived 5mC MEs partially mediated the association between FEH and right hippocampal volume (Burlywood ME indirect effect b = - 111, p = 0.014), and fully mediated the FEH and right amygdala volume relationship (Pink4 ME indirect effect b = - 48, p = 0.026). Modules were enriched with probes falling in genes with immune, central nervous system (CNS), cellular development/differentiation, and metabolic functions. CONCLUSIONS: Findings extend work highlighting neurodevelopmental variability associated with adverse social environment exposure during childhood by specifically implicating poor FEH, while informing a mechanism of biological embedding. FEH-associated epigenetic signatures could function as proxies of altered fronto-limbic grey matter volume associated with poor childhood FEH and inform further investigation into primarily affected tissues such as endocrine, immune, and CNS cell types.

Child Sexual Abuse as a Unique Risk Factor for the Development of Psychopathology: The Compounded Convergence of Mechanisms.

Meta-analytic, population cohort, prospective, and clinical studies provide systematic evidence that child sexual abuse accounts for unique variation in several deleterious outcomes. There is strong evidence for psychiatric disorders, including posttraumatic stress disorder and mood, anxiety, and substance use disorders, and mixed evidence for personality disorders. Evaluation of sex-specific outcomes shows strong evidence for teenage childbearing, sexual revictimization, and sexual dysfunction and mixed evidence for heightened sexual behaviors and sexual offending. This review further demonstrates not only that survivors suffer the noxious impact of traumatic sexualization but that additional transdiagnostic mechanisms, including the biological embedding of stress, emotion dysregulation, avoidance, and insecure attachment, converge to compound risk for deleterious outcomes. A road map to enhance the rigor of future research is outlined, and specific recommendations for evidence-based policy making to boost prevention efforts and increase access to treatment are discussed.