Measuring Toxic Stress in Childhood and Youth: A Systematic Review.

INTRODUCTION: Toxic stress among children/youth is a significant public health concern that has been linked to serious morbidities and premature mortality in adulthood. Uniformity in measurement of a toxic stress variable for use in scholarly research can aid in a more comprehensive understanding of its indicators and implications. METHOD: The purpose of this systematic review was to aggregate, organize, and summarize the literature around current practices for operationalizing toxic stress among children/youth. A strategic methodology was conducted according to PRISMA guidelines, and two databases were consulted for relevant studies. RESULTS: Over 30 different measurement tools were identified across 13 included studies, ranging from biomarkers and physiological indicators to scales, diagnoses, and other assessment instruments. DISCUSSION: By synthesizing current measurement methods, this review informs research and clinical communities of different approaches to toxic stress measurement, advances standardization efforts, and justifies the necessity of a singular, scientifically validated tool.

Gut microbiota mediate early life stress-induced social dysfunction and anxiety-like behaviors by impairing amino acid transport at the gut.

Early life stress alters gut microbiota and increases the risk of neuropsychiatric disorders, including social deficits and anxiety, in the host. However, the role of gut commensal bacteria in early life stress-induced neurobehavioral abnormalities remains unclear. Using the maternally separated (MS) mice, our research has unveiled a novel aspect of this complex relationship. We discovered that the reduced levels of amino acid transporters in the intestine of MS mice led to low glutamine (Gln) levels in the blood and synaptic dysfunction in the medial prefrontal cortex (mPFC). Abnormally low blood Gln levels limit the brain's availability of Gln, which is required for presynaptic glutamate (Glu) and γ-aminobutyric acid (GABA) replenishment. Furthermore, MS resulted in gut microbiota dysbiosis characterized by a reduction in the relative abundance of Lactobacillus reuteri (L. reuteri). Notably, supplementation with L. reuteri ameliorates neurobehavioral abnormalities in MS mice by increasing intestinal amino acid transport and restoring synaptic transmission in the mPFC. In conclusion, our findings on the role of L. reuteri in regulating intestinal amino acid transport and buffering early life stress-induced behavioral abnormalities provide a novel insight into the microbiota-gut-brain signaling basis for emotional behaviors.

Infant Temperament Is Associated With Milk Cortisol but Not With Maternal Childhood Trauma.

Previous studies have suggested that maternal childhood trauma (MCT) may influence infant temperament, but the underlying physiological mechanisms remain unclear. This study sought to confirm the involvement of breast milk cortisol in the link between MCT and infant temperament. The study sample included 90 mother-infant dyads recruited from the urban Polish population. MCT was assessed based on the Early Life Stress Questionnaire (ELSQ) and infant temperamental factors (surgency/extraversion, negative affectivity, and orienting/regulation) using the Infant Behavior Questionnaire-Revised at 12 months of life. Cortisol was assayed in milk samples collected at 5 months of life using the ELISA method. Based on the ELSQ median, the sample was divided into low and high MCT groups. The ANCOVA models with milk cortisol as a covariant were run to check the effect of low versus high MCT on infant temperament. We found a positive association between milk cortisol and orienting/regulation. Surprisingly, the low and high MCT groups did not significantly differ in milk cortisol. Furthermore, we found that MCT was unrelated to any infant temperamental factor. While recent literature on the association between milk cortisol and infant temperament is inconsistent, our results suggest that high orienting/regulation might be an adaptation to adverse environments such as stress. Moreover, the infant's temperament appears to be more responsive to the current exposition to maternal stress than her experience of traumatic stress.

Early life stress exacerbates the obesogenic and anxiogenic effects of a Western diet without worsening cardiac ischaemic tolerance in male mice.

Early life stress (ELS) and a Western diet (WD) promote mood and cardiovascular disorders, however, how these risks interact in disease pathogenesis is unclear. We assessed effects of ELS with or without a subsequent WD on behaviour, cardiometabolic risk factors, and cardiac function/ischaemic tolerance in male mice. Fifty-six new-born male C57BL/6J mice were randomly allocated to a control group (CON) undisturbed before weaning, or to maternal separation (3h/day) and early (postnatal day 17) weaning (MSEW). Mice consumed standard rodent chow (CON, n = 14; MSEW, n = 15) or WD chow (WD, n = 19; MSEW + WD, n = 19) from week 8 to 24. Fasted blood was sampled and open field test and elevated plus maze (EPM) tests undertaken at 7, 15, and 23 weeks of age, with hearts excised at 24 weeks for Langendorff perfusion (evaluating pre- and post-ischaemic function). MSEW alone transiently increased open field activity at 7 weeks; body weight and serum triglycerides at 4 and 7 weeks, respectively; and final blood glucose levels and insulin resistance at 23 weeks. WD increased insulin resistance and body weight gain, the latter potentiated by MSEW. MSEW + WD was anxiogenic, reducing EPM open arm activity vs. WD alone. Although MSEW had modest metabolic effects and did not influence cardiac function or ischaemic tolerance in lean mice, it exacerbated weight gain and anxiogenesis, and improved ischaemic tolerance in WD fed animals. MSEW-induced increases in body weight (obesity) in WD fed animals in the absence of changes in insulin resistance may have protected the hearts of these mice.

Perineuronal Net Alterations Following Early-Life Stress: Are Microglia Pulling Some Strings?

The extracellular matrix plays a key role in synapse formation and in the modulation of synaptic function in the central nervous system. Recent investigations have revealed that microglia, the resident immune cells of the brain, are involved in extracellular matrix remodeling under both physiological and pathological conditions. Moreover, the dysregulation of both innate immune responses and the extracellular matrix has been documented in stress-related psychopathologies as well as in relation to early-life stress. However, the dynamics of microglial regulation of the ECM and how it can be impacted by early-life adversity have been understudied. This brief review provides an overview of the recent literature on this topic, drawing from both animal model and human post mortem studies. Direct and indirect mechanisms through which microglia may regulate the extracellular matrix-including perineuronal nets-are presented and discussed in light of the interactions with other cell types.

Role of stress and early-life stress in the pathogeny of inflammatory bowel disease.

Numerous preclinical and clinical studies have shown that stress is one of the main environmental factor playing a significant role in the pathogeny and life-course of bowel diseases. However, stressful events that occur early in life, even during the fetal life, leave different traces within the central nervous system, in area involved in stress response and autonomic network but also in emotion, cognition and memory regulation. Early-life stress can disrupt the prefrontal-amygdala circuit thus favoring an imbalance of the autonomic nervous system and the hypothalamic-pituitary adrenal axis, resulting in anxiety-like behaviors. The down regulation of vagus nerve and cholinergic anti-inflammatory pathway favors pro-inflammatory conditions. Recent data suggest that emotional abuse at early life are aggravating risk factors in inflammatory bowel disease. This review aims to unravel the mechanisms that explain the consequences of early life events and stress in the pathophysiology of inflammatory bowel disease and their mental co-morbidities. A review of therapeutic potential will also be covered.

Analysis of hippocampal synaptic function in a rodent model of early life stress.

Background: Early life stress (ELS) is an important risk factor in the aetiology of depression. Developmental glucocorticoid exposure impacts multiple brain regions with the hippocampus being particularly vulnerable. Hippocampal mediated behaviours are dependent upon the ability of neurones to undergo long-term potentiation (LTP), an N-methyl-D-aspartate receptor (NMDAR) mediated process. In this study we investigated the effect of ELS upon hippocampal NMDAR function. Methods: Hooded Long-Evans rat pups (n=82) were either undisturbed or maternally separated for 180 minutes per day (MS180) between post-natal day (PND) 1 and PND14. Model validation consisted of sucrose preference (n=18) and novelty supressed feeding (NSFT, n=34) tests alongside assessment of corticosterone (CORT) and paraventricular nucleus (PVN) cFos reactivity to stress and hippocampal neurogenesis (all n=18). AMPA/NMDA ratios (n=19), miniEPSC currents (n=19) and LTP (n=15) were assessed in whole-cell patch clamp experiments in CA1 pyramidal neurones. Results: MS180 animals showed increased feeding latency in the NSFT alongside increased overall CORT in the restraint stress experiment and increased PVN cFos expression in males but no changes in neurogenesis or sucrose preference. MS180 was associated with a lower AMPA/NMDA ratio with no change in miniEPSC amplitude or area. There was no difference in short- or long-term potentiation between MS180 and control animals nor were there any changes during the induction protocol. Conclusions: The MS180 model showed a behavioural phenotype consistent with previous work. MS180 animals showed increased NMDAR function with preliminary evidence suggesting that this was not concurrent with an increase in LTP.

Highly stressful early life events are the biggest risk factor for developing depression in adulthood. The hippocampus is a brain region that is highly susceptible to this stress and is crucial for coordinating learning and memory which underpins many aspects of cognitive function. Our study investigated if changes in the way that the neurons in the hippocampus communicate could provide explanations as to why early life stress predisposes to depression. We used an animal model of early life stress where rat pups are separated from their mother for three hours per day during their early life. Upon adulthood this resulted in the rats being slower to eat food in a new environment, a standard test of anxiety behaviour. We then used a technique called ex-vivo patch clamp electrophysiology to study how the individual neurons in their hippocampi and their connections functioned after early life stress. We measured the relative power of the signals from two key synaptic receptors essential for communication between neurons: AMPA and NMDA receptors. AMPA receptors are the key receptors enabling communication between neurons at synapses whereas NMDA receptors allow a neuron to become more sensitive to input signals and adapt synaptic strength. Animals with early life stress had more NMDA receptor function relative to AMPA function compared to control animals. We used a technique called miniEPSC recordings to rule out any change in AMPA receptor function in ELS animals meaning an effect specific to NMDA receptors. However, we found no changes to the ability for synapses to adapt their strength between groups. This work presents evidence for changes in hippocampal neurons and synapses caused by early life stress but further work is needed to understand how this relates to depression.

Early life stress and iron metabolism in developmental psychoneuroimmunology.

An estimated 250 million children face adverse health outcomes from early life exposure to severe or chronic social, economic, and nutritional adversity, highlighting/emphasizing the pressing concern about the link between ELS and long-term implications on mental and physical health. There is significant overlap between populations experiencing high levels of chronic stress and those experiencing iron deficiency, spotlighting the potential role of iron as a key mediator in this association. Iron, an essential micronutrient for brain development and immune function, is often depleted in stress conditions. Iron deficiency among the most common nutrient deficiencies in the world. Fetal and infant iron status may thus serve as a crucial intermediary between early chronic psychological stress and subsequent immune system changes to impact neurodevelopment. The review presents a hypothesized pathway between early life stress (ELS), iron deficiency, and neurodevelopment through the hypothalamic-pituitary-adrenocortical (HPA) axis and the IL-6-hepcidin axis. This hypothesis is derived from (1) evidence that stress impacts iron status (2) long-term neurodevelopmental outcomes that are shared by ELS and iron deficiency exposure, and (3) possible mechanisms for how iron may mediate the relation between ELS and iron deficiency through alterations in the developing immune system. The article concludes by proposing future research directions, emphasizing the need for rigorous studies to elucidate how stress and iron metabolism interact to modify the developing immune system. Understanding these mechanisms could open new avenues for improving human health and neurodevelopment for women and children globally, making it a timely and vital area of study in psychoneuroimmunology research.

Childhood maltreatment and the risk of eating disorders: a meta-analysis of observational studies.

OBJECTIVE: The purpose of this systematic review and meta-analysis is to examine the relationship between childhood maltreatment as a variable of exposure and eating disorders as an outcome. METHODS: PubMed, Web of Science, and Google Scholar were searched to find manuscripts related to the current research. The search was conducted up until October 2023 and limited to the English language. An odds ratio (OR) based on the random effects method was used to combine studies. One subgroup analysis was performed based on the type of eating disorder and another based on the type of childhood maltreatment. RESULTS: Thirty eligible studies were recognized for this research. Childhood maltreatment was associated with a rate of eating disorders of more than double: OR 2.37 with 95% confidence interval (CI) 1.84-3.06 (P < 0.001; I2 = 92.6%). Childhood maltreatment was associated with anorexia nervosa (OR 1.89, 95% CI 1.47-2.42; Z = 5.03; P < 0.001; I2 = 0%), bulimia nervosa (OR 2.64, 95% CI 1.34-5.17; Z = 2.82; P = 0.005; I2 = 93.1%), and binge eating disorder (OR 1.76, 95% CI 1.38-2.26; Z = 4.52; P < 0.001; I2 = 80.2%). CONCLUSION: The findings of this research showed that childhood maltreatment significantly increases the risk of eating disorders. Therefore, in understanding the mechanisms related to eating disorders, it is necessary to pay attention to the issue of the childhood living environment and the traumatic experiences of that time.

Late maternal separation provides resilience to chronic variable stress-induced anxiety- and depressive-like behaviours in male but not female mice.

Maternal separation can have long-lasting effects on an individual's susceptibility to stress later in life. Maternal separation during the postnatal period is a commonly used paradigm in rodents to investigate the effects of early life stress on neurobehavioural changes and stress responsiveness. However, maternal separation during stress hyporesponsive and responsive periods of postnatal development may differ in its effects on stress resilience. Therefore, we hypothesised that late maternal separation (LMS) from postnatal day 10 to 21 in mice may have different effect on resilience than early maternal separation during the first week of postnatal life. Our results suggested that male LMS mice are more resilient to chronic variable stress (CVS)-induced anxiety and depressive-like behaviour as confirmed by the open field, light-dark field, elevated plus maze, sucrose preference and tail suspension tests. In contrast, female LMS mice were equally resilient as non-LMS female mice. We found increased expression of NPY, NPY1R, NPY2R, NPFFR1, and NPFFR2 in the hypothalamus of male LMS mice whereas the opposite effect was observed in the hippocampus. LMS in male and female mice did not affect circulating corticosterone levels in response to psychological or physiological stressors. Thus, LMS renders male mice resilient to CVS-induced neurobehavioural disorders in adulthood.

Sexual dimorphism exists in the effects of late maternal separation (LMS)LMS provides resilience to stress-induced anxiety and depression in male miceLMS upregulates NPY and NPVF system in the hypothalamus of male miceNo effect of LMS on stress-induced corticosterone levels.

Maternal separation as early-life stress: Mechanisms of neuropsychiatric disorders and inspiration for neonatal care.

The establishment of positive early parent-infant relationships provide essential nourishment and social stimulation for newborns. During the early stages of postnatal brain development, events such as synaptogenesis, neuronal maturation and glial differentiation occur in a highly coordinated manner. Maternal separation, as an early-life stress introducer, can disrupt the formation of parent-child bonds and exert long-term adverse effects throughout life. When offspring are exposed to maternal separation, the body regulates the stress of maternal separation through multiple mechanisms, including neuroinflammatory responses, neuroendocrinology, and neuronal electrical activity. In adulthood, early maternal separation has long-term effects, such as the induction of neuropsychiatric disorders such as anxiety, depression, and cognitive dysfunction. This review summarized the application of maternal separation models and the mechanisms of stress system response in neuropsychiatric disorders, serving as both a reminder and inspiration for approaches to improve neonatal care, "from bench to bedside".

Defining and distinguishing early life stress, trauma, adversity, toxic and chronic stress and allostatic load: a descriptive review.

AIMS: Various concepts are used to study the impact of stress on childhood development. These concepts are often used inconsistently or interchangeably. Our main objectives were to determine how selected stress concepts (chronic stress, toxic stress, allostatic load, early life stress, childhood adversity, childhood trauma and adverse childhood experiences; ACEs) are defined, operationalized and described, and to provide a theoretical context to aid the choice for a preferred concept in public health research. METHODS: For this descriptive review, we systematically searched for literature published before 4 August 2021, on PubMed, Embase and PsycInfo. Two independent reviewers included studies. Exclusion criteria were: no systematic review, not peer reviewed, not published in English, selected stress concepts were no predetermined variable or a substantial topic in the discussion, full text was unobtainable or study described non-human or non-childhood populations. Data extraction forms were used. Descriptives were gathered, publication fields were identified through Journal Citation Reports categories, and verbatim descriptions were ordered in text and Venn diagrams. RESULTS: Of 264 screened studies, 124 were included. ACEs, childhood adversity and childhood trauma were used most. ACEs were the main concept used most frequently (47.6%). A total of 11 of 14 public and environmental health journals used ACEs. All concepts refer to prolonged, repeated, interpersonal stress from 0 to 18 years, that can alter physiological systems. Four concepts were stressor oriented, two concepts focused on stress response and effect and one on the state of challenged homeostasis. CONCLUSIONS: ACEs seem most fitting for public health setting, due to their operationalizability, large set of core experiences and widespread use.

Paternal adverse childhood experiences are associated with a low risk of atopy in the offspring.

AIM: Parental adverse childhood experiences (ACE) might affect the offspring health through intergenerational inheritance. The aim of this study was to investigate how paternal ACE associate with offspring sensitisation and allergic rhinitis (AR). METHODS: The study included 590 Finnish father-child dyads from the FinnBrain Birth Cohort Study. Outcomes were offspring sensitisation against allergens and AR at age 5.5 years. Paternal ACE up to 18 years were assessed using the Trauma and Distress Scale (TADS) with the lowest quarter as the reference group. RESULTS: Of the children, 317 (54%) were males. Sensitisation occurred in 162/533 (30%) and AR in 122/590 (21%). Paternal TADS (median 17 points; interquartile range 11-27) was inversely associated with the risk of sensitisation. Children whose fathers scored the highest quarter had the lowest risk of sensitisation (adjusted odds ratio 0.42; 95% confidence interval 0.24-0.75), followed by those in the second highest quarter (0.58; 0.34-0.99). The association between the highest quarter and reduced risk of AR was similar. CONCLUSION: Paternal ACE were associated with a low risk of offspring sensitisation and AR, suggesting paternal childhood stress might influence immune responses in their offspring.

Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic-pituitary-adrenal-axis dysregulation: a study protocol description.

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.

Mono-methylation of lysine 27 at histone 3 confers lifelong susceptibility to stress.

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility.

Influence of Diet on Reproducible Corticosterone Levels in a Mouse Model of Maternal Separation with Early Weaning.

Maternal separation with early weaning (MSEW) is a popular early life stress (ELS) model in rodents, which emulates childhood neglect through scheduled mother-offspring separation. Although variations of ELS models, including maternal separation and MSEW, have been published for the mouse species, the reported results are inconsistent. Corticosterone is considered the main stress hormone involved in regulating stress responses in rodents-yet generating a robust and reproducible corticosterone response in mouse models of ELS has been elusive. Considering the current lack of standardization for MSEW protocols, these inconsistent results may be attributed to variations in model methodologies. Here, we compared the effects of select early wean diet sources-which are the non-milk diets used to complete early weaning in MSEW pups-on the immediate stress phenotype of C57BL/6J mice at postnatal day 21. Non-aversive handling was an integral component of our modified MSEW model. The evaluation of body weight and serum corticosterone revealed the early wean diet to be a key variable in the resulting stress phenotype. Interestingly, select non-milk diets facilitated a stress phenotype in which low body weight was accompanied by significant corticosterone elevation. Our data indicate that dietary considerations are critical in MSEW-based studies and provide insight into improving the reproducibility of key stress-associated outcomes as a function of this widely used ELS paradigm.

Developmental functions of microglia: Impact of psychosocial and physiological early life stress.

Microglia play numerous important roles in brain development. From early embryonic stages through adolescence, these immune cells influence neuronal genesis and maturation, guide connectivity, and shape brain circuits. They also interact with other glial cells and structures, influencing the brain's supportive microenvironment. While this central role makes microglia essential, it means that early life perturbations to microglia can have widespread effects on brain development, potentially resulting in long-lasting behavioral impairments. Here, we will focus on the effects of early life psychosocial versus physiological stressors in rodent models. Psychosocial stress refers to perceived threats that lead to stress axes activation, including prenatal stress, or chronic postnatal stress, including maternal separation and resource scarcity. Physiological stress refers to physical threats, including maternal immune activation, postnatal infection, and traumatic brain injury. Differing sources of early life stress have varied impacts on microglia, and these effects are moderated by factors such as developmental age, brain region, and sex. Overall, these stressors appear to either 1) upregulate basal microglia numbers and activity throughout the lifespan, while possibly blunting their responsivity to subsequent stressors, or 2) shift the developmental curve of microglia, resulting in differential timing and function, impacting the critical periods they govern. Either could contribute to behavioral dysfunctions that occur after the resolution of early life stress. Exploring how different stressors impact microglia, as well as how multiple stressors interact to alter microglia's developmental functions, could deepen our understanding of how early life stress changes the brain's developmental trajectory. This article is part of the Special Issue on "Microglia".

Childhood trauma is linked to epigenetic age deceleration in young adults with previous youth residential care placements.

Background: Early adversity increases the risk for mental and physical disorders as well as premature death. Epigenetic processes, and altered epigenetic aging in particular, might mediate these effects. While the literature that examined links between early adversity and epigenetic aging is growing, results have been heterogeneous.Objective: In the current work, we explored the link between early adversity and epigenetic aging in a sample of formerly out-of-home placed young adults.Method: A total of N = 117 young adults (32% women, age mean = 26.3 years, SD = 3.6 years) with previous youth residential care placements completed the Childhood Trauma Questionnaire (CTQ) and the Life Events Checklist (LEC-R) and provided blood samples for the analysis of DNA methylation using the Illumina Infinium MethylationEPIC BeadChip Microarray. Epigenetic age was estimated using Hovarth's and Hannum's epigenetic clocks. Furthermore, Hovarth's and Hannum's epigenetic age residuals were calculated as a proxy of epigenetic aging by regressing epigenetic age on chronological age. The statistical analysis plan was preregistered (https://osf.io/b9ev8).Results: Childhood trauma (CTQ) was negatively associated with Hannum's epigenetic age residuals, ß = -.23, p = .004 when controlling for sex, BMI, smoking status and proportional white blood cell type estimates. This association was driven by experiences of physical neglect, ß = -.25, p = .001. Lifetime trauma exposure (LEC-R) was not a significant predictor of epigenetic age residuals.Conclusion: Childhood trauma, and physical neglect in particular, was associated with decelerated epigenetic aging in our sample. More studies focusing on formerly institutionalized at-risk populations are needed to better understand which factors affect stress-related adaptations following traumatic experiences.

Growing literature links early adversity to altered epigenetic aging, yet results have been heterogeneous.We assessed childhood and lifetime trauma exposure using the Childhood Trauma Questionnaire and the Life Events Checklist and estimated epigenetic aging by obtaining Horvath's and Hannum's epigenetic age residuals in a sample of formerly out-of-home placed young adults.In this high-risk sample, childhood trauma, physical neglect in particular, but not lifetime trauma was negatively related to epigenetic aging.

Individual longitudinal changes in DNA-methylome identify signatures of early-life adversity and correlate with later outcome.

Adverse early-life experiences (ELA) affect a majority of the world's children. Whereas the enduring impact of ELA on cognitive and emotional health is established, there are no tools to predict vulnerability to ELA consequences in an individual child. Epigenetic markers including peripheral-cell DNA-methylation profiles may encode ELA and provide predictive outcome markers, yet the interindividual variance of the human genome and rapid changes in DNA methylation in childhood pose significant challenges. Hoping to mitigate these challenges we examined the relation of several ELA dimensions to DNA methylation changes and outcome using a within-subject longitudinal design and a high methylation-change threshold. DNA methylation was analyzed in buccal swab/saliva samples collected twice (neonatally and at 12 months) in 110 infants. We identified CpGs differentially methylated across time for each child and determined whether they associated with ELA indicators and executive function at age 5. We assessed sex differences and derived a sex-dependent 'impact score' based on sites that most contributed to methylation changes. Changes in methylation between two samples of an individual child reflected age-related trends and correlated with executive function years later. Among tested ELA dimensions and life factors including income to needs ratios, maternal sensitivity, body mass index and infant sex, unpredictability of parental and household signals was the strongest predictor of executive function. In girls, high early-life unpredictability interacted with methylation changes to presage executive function. Thus, longitudinal, within-subject changes in methylation profiles may provide a signature of ELA and a potential predictive marker of individual outcome.

Perinatal protein malnutrition alters maternal behavior and leads to maladaptive stress response, neurodevelopmental delay and disruption on DNA methylation machinery in female mice offspring.

Deficiencies in maternal nutrition have long-term consequences affecting brain development of the progeny and its behavior. In the present work, female mice were exposed to a normal-protein or a low-protein diet during gestation and lactation. We analyzed behavioral and molecular consequences of malnutrition in dams and how it affects female offspring at weaning. We have observed that a low-protein diet during pregnancy and lactation leads to anxiety-like behavior and anhedonia in dams. Protein malnutrition during the perinatal period delays physical and neurological development of female pups. Glucocorticoid levels increased in the plasma of malnourished female offspring but not in dams when compared to the control group. Interestingly, the expression of glucocorticoid receptor (GR) was reduced in hippocampus and amygdala on both malnourished dams and female pups. In addition, malnourished pups exhibited a significant increase in the expression of Dnmt3b, Gadd45b, and Fkbp5 and a reduction in Bdnf VI variant mRNA in hippocampus. In contrast, a reduction on Dnmt3b has been observed on the amygdala of weaned mice. No changes have been observed on global methylation levels (5-methylcytosine) in hippocampal genomic DNA neither in dams nor female offspring. In conclusion, deregulated behaviors observed in malnourished dams might be mediated by a low expression of GR in brain regions associated with emotive behaviors. Additionally, low-protein diet differentially deregulates the expression of genes involved in DNA methylation/demethylation machinery in female offspring but not in dams, providing an insight into regional- and age-specific mechanisms due to protein malnutrition.