Biological embedding of childhood adversity: from physiological mechanisms to clinical implications.
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ABSTRACT:
SUBMITTER: Berens AE
PROVIDER: S-EPMC5518144 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:Early life social experiences are believed to confer persistent effects on individual’s biology and subsequent functioning and health. Using a diverse, longitudinal community sample of 178 children, we show that three different types of early life social experience: family income, parental education, and family psychosocial adversity, each predict DNA methylation within buccal epithelial cells. Each predictor was significantly associated with DNA methylation within a unique set of genomic CpG sites, with income showing the greatest number of associations. Findings were independently verified using pyrosequencing. Our results provide evidence for longitudinal associations between early life social environment and variation in DNA methylation during childhood, after adjusting for genetic ancestry and self-reported ethnic minority status. Gene ontology analyses of top, differentially methylated CpG sites point to genes serving immune and developmental regulation functions, suggesting potential pathways for the biological embedding of early life stress and its association with later development and health.
2018-12-07 | GSE94734 | GEO
Project description:Is childhood adversity associated with biological aging, and if so, does sex modify the association, and do lifestyle and mental health mediate the association? A lifespan analysis is conducted using data on 142 872 participants from the UK Biobank to address these questions. Childhood adversity is assessed through the online mental health questionnaire (2016), including physical neglect, physical abuse, emotional neglect, emotional abuse, sexual abuse, and a cumulative score. Biological aging is indicated by telomere length (TL) measured from leukocyte DNA using qPCR, and the shorter TL indicates accelerated biological aging; a lifestyle score is constructed using body mass index, physical activity, drinking, smoking, and diet; mental disorder is assessed using depression, anxiety, and insomnia at the baseline survey. The results reveal a sex-specific association such that childhood adversity is associated with shorter TL in women after adjusting for covariates including polygenic risk score for TL, but not in men. Unhealthy lifestyle and mental disorder partially mediate the association in women. The proportions of indirect effects are largest for sexual and physical abuse. These findings highlight the importance of behavioral and psychological interventions in promoting healthy aging among women who experienced childhood adversity, particularly sexual and physical abuse.
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Project description:Adverse childhood experiences have been consistently linked with physical and mental health disorders in adulthood that may be mediated, in part, via the effects of such exposures on biological aging. Using recently developed "epigenetic clocks", which provide an estimate of biological age, several studies have demonstrated a link between the cumulative exposure to childhood adversities and accelerated epigenetic aging. However, not all childhood adversities are equivalent and less is known about how distinct dimensions of childhood adversity relate to epigenetic aging metrics. Using two measures of childhood adversity exposure, we assess how the dimensions of Maltreatment and Household Dysfunction relate to epigenetic aging using two "second-generation" clocks, GrimAge and PhenoAge, in a cohort of unmedicated somatically healthy adults with moderate to severe major depression (n = 82). Our results demonstrate that the dimension of Maltreatment is associated with epigenetic age acceleration (EAA) using the PhenoAge but not the GrimAge clock. This association was observed using both the Childhood Trauma questionnaire (CTQ; β = 0.272, p = 0.013) and the Adverse Childhood Experiences (ACEs) questionnaire (β = 0.307, p = 0.005) and remained significant when adjusting for exposure to the dimension of Household Dysfunction (β = 0.322, p = 0.009). In contrast, the dimension of Household Dysfunction is associated with epigenetic age deceleration (β = -0.194, p = 0.083) which achieved significance after adjusting for exposure to the dimension of Maltreatment (β = -0.304, p = 0.022). This study is the first to investigate these effects among individuals with Major Depressive Disorder and suggests that these dimensions of adversity may be associated with disease via distinct biological mechanisms.
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Project description:The discovery of hepcidin has provided a solid foundation for understanding the mechanisms of systemic iron homeostasis and the aetiologies of iron disorders. Hepcidin assures the balance of circulating and stored iron levels for multiple physiological processes including oxygen transport and erythropoiesis, while limiting the toxicity of excess iron. The liver is the major site where regulatory signals from iron, erythropoietic drive and inflammation are integrated to control hepcidin production. Pathologically, hepcidin dysregulation by genetic inactivation, ineffective erythropoiesis, or inflammation leads to diseases of iron deficiency or overload such as iron-refractory iron-deficiency anaemia, anaemia of inflammation, iron-loading anaemias and hereditary haemochromatosis. In the present review, we discuss recent insights into the molecular mechanisms governing hepcidin regulation, how these pathways are disrupted in iron disorders, and how this knowledge is being used to develop novel diagnostic and therapeutic strategies.
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Project description:BackgroundChildhood adversity has been previously associated with alterations in brain structure, but heterogeneous designs, methods, and measures have contributed to mixed results and have impeded progress in mapping the biological embedding of childhood adversity. We sought to identify long-term differences in structural brain integrity associated with childhood adversity.MethodsMultiple regression was used to test associations between prospectively ascertained adversity during childhood and adversity retrospectively reported in adulthood with structural magnetic resonance imaging measures of midlife global and regional cortical thickness, cortical surface area, and subcortical gray matter volume in 861 (425 female) members of the Dunedin Study, a longitudinal investigation of a population-representative birth cohort.ResultsBoth prospectively ascertained childhood adversity and retrospectively reported adversity were associated with alterations in midlife structural brain integrity, but associations with prospectively ascertained childhood adversity were consistently stronger and more widely distributed than associations with retrospectively reported childhood adversity. Sensitivity analyses revealed that these associations were not driven by any particular adversity or category of adversity (i.e., threat or deprivation) or by childhood socioeconomic disadvantage. Network enrichment analyses revealed that these associations were not localized but were broadly distributed along a hierarchical cortical gradient of information processing.ConclusionsExposure to childhood adversity broadly is associated with widespread differences in midlife gray matter across cortical and subcortical structures, suggesting that biological embedding of childhood adversity in the brain is long lasting, but not localized. Research using retrospectively reported adversity likely underestimates the magnitude of these associations. These findings may inform future research investigating mechanisms through which adversity becomes embedded in the brain and influences mental health and cognition.
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Project description: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.
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Project description:Multiple BRAF inhibitor resistance mechanisms have been described, however their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma. Excised progressing BRAFV600 mutant melanoma metastases (Prog) from patients treated with dabrafenib (n=22) or vemurafenib (n=8) were analyzed for known resistance mechanisms. Oncogenic signaling in Prog and matched pre-treatment tumors was examined using gene expression analysis. Resistance mechanisms were correlated with clinicopathologic features and outcome. A resistance mechanism was identified in 21/38 (55%) Prog samples from 30 patients; BRAF splice variants (n=12, 32%), N-RAS mutations (n=3, 8%), BRAF amplification (n=3, 8%), MEK1/2 mutations (n=3, 8%) and an AKT1 mutation (n=1, 3%). Four Progs tumours displayed multiple resistance mechanisms, and four patients with multiple Progs demonstrated inter-tumoral heterogeneity of resistance mechanisms. Six (21%) of 29 Progs showed loss of MAPK activity by gene expression analysis. These MAPK-inhibited Progs had unknown resistance mechanisms, and these patients had a shorter progression-free survival than patients with MAPK re-activated Progs. There were no responses to subsequent targeted therapy, even when the identified mechanism of resistance was predicted to be responsive. Heterogeneity of resistance mechanisms was common between patients, within patients and within individual tumors. The MAPK pathway remained inhibited in a subset of resistant tumors with unknown mechanisms of resistance, and the outcomes of patients with these tumors are poor. The use of sequential targeted therapies based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved clinical outcomes. Total RNA was obtained from fresh-frozen melanoma tumour samples from patients before commencing treatment with dabrafenib or vemurafenib and at time of tumour progression.
2014-02-19 | E-GEOD-50509 | biostudies-arrayexpress
Project description:Multiple BRAF inhibitor resistance mechanisms have been described, however their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma. Excised progressing BRAFV600 mutant melanoma metastases (Prog) from patients treated with dabrafenib (n=22) or vemurafenib (n=8) were analyzed for known resistance mechanisms. Oncogenic signaling in Prog and matched pre-treatment tumors was examined using gene expression analysis. Resistance mechanisms were correlated with clinicopathologic features and outcome. A resistance mechanism was identified in 21/38 (55%) Prog samples from 30 patients; BRAF splice variants (n=12, 32%), N-RAS mutations (n=3, 8%), BRAF amplification (n=3, 8%), MEK1/2 mutations (n=3, 8%) and an AKT1 mutation (n=1, 3%). Four Progs tumours displayed multiple resistance mechanisms, and four patients with multiple Progs demonstrated inter-tumoral heterogeneity of resistance mechanisms. Six (21%) of 29 Progs showed loss of MAPK activity by gene expression analysis. These MAPK-inhibited Progs had unknown resistance mechanisms, and these patients had a shorter progression-free survival than patients with MAPK re-activated Progs. There were no responses to subsequent targeted therapy, even when the identified mechanism of resistance was predicted to be responsive. Heterogeneity of resistance mechanisms was common between patients, within patients and within individual tumors. The MAPK pathway remained inhibited in a subset of resistant tumors with unknown mechanisms of resistance, and the outcomes of patients with these tumors are poor. The use of sequential targeted therapies based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved clinical outcomes.
2014-02-19 | GSE50509 | GEO
Project description:Experiencing an adverse childhood and parental neglect is a risk factor for depression in the adult population. Patients with a history of traumatic childhood develop a subtype of depression that is characterized by earlier onset, poor treatment response and more severe symptoms. The long-lasting molecular mechanisms that are engaged during early traumatic events and determine the risk for depression are poorly understood. In this study, we altered adult depression-like behavior in mice by applying juvenile isolation stress. We found that this behavioral phenotype was associated with a reduction in the levels of the deacetylase sirtuin1 (SIRT1) in the brain and in peripheral blood mononuclear cells. Notably, peripheral blood mRNA expression of SIRT1 predicted the extent of behavioral despair only when depression-like behavior was induced by juvenile--but not adult--stress, implicating SIRT1 in the regulation of adult behavior at early ages. Consistent with this hypothesis, pharmacological modulation of SIRT1 during juvenile age altered the depression-like behavior in naive mice. We also performed a pilot study in humans, in which the blood levels of SIRT1 correlated significantly with the severity of symptoms in major depression patients, especially in those who received less parental care during childhood. On the basis of these novel findings, we propose the involvement of SIRT1 in the long-term consequences of adverse childhood experiences.
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Project description:ObjectiveThe study aims to evaluate the association between exposure to childhood adversity and insomnia, with an emphasis on the role of adversity type, timing, and accumulation (i.e., the number of specific types of adversities the child reported being exposed to).MethodsOur analytic sample comprised 9582 adolescents from the National Comorbidity Survey Replication Adolescent Supplement (NCS-A), a nationally representative population-based sample. We examined the association between 18 different types of retrospectively reported adversities (capturing interpersonal violence, accidents and injuries, social network or witnessing events, and other adverse events) and risk of self-reported past-year insomnia. We also examined whether the age at first exposure to adversity was associated with the risk of insomnia, and whether exposure to a greater number of different types of adversities (ie, accumulation) conferred an elevated risk of insomnia. In addition, we performed a sensitivity analysis excluding adolescents with a past-year diagnosis of major depression, dysthymia, post-traumatic stress disorder (PTSD), or generalized anxiety disorder.ResultsAlmost one-third of adolescents reported insomnia, with a higher prevalence among girls and those from racial/ethnic minority groups. Adolescents exposed to at least one childhood adversity of any type (59.41%) were more likely than their nonexposed peers to experience insomnia (across adversities, prevalence ratios (PRs) ranged from 1.31 to 1.89). Risk of insomnia differed based on the age at first exposure to adversity as well as the type of adversity. Adolescents exposed to a greater number of different types of adversities had a higher risk of insomnia compared to those experiencing fewer adversities. These results were similar, by and large, to those obtained after excluding adolescents with at least one of the four past-year psychiatric disorders.ConclusionsExposure to adversity confers an elevated risk of insomnia. This association varied by type, timing, and accumulation of exposure and did not appear to be driven by psychiatric disorders. Given the well-documented physical and mental health consequences of insomnia, such findings further support the need for practitioners to screen children for exposure to childhood adversity and insomnia symptoms.
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