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The effects of childhood maltreatment on epigenetic regulation of stress-response associated genes: an intergenerational approach.

ABSTRACT: While biological alterations associated with childhood maltreatment (CM) have been found in affected individuals, it remains unknown to what degree these alterations are biologically transmitted to the next generation. We investigated intergenerational effects of maternal CM on DNA methylation and gene expression in N?=?113 mother-infant dyads shortly after parturition, additionally accounting for the role of the FKBP5 rs1360780 genotype. Using mass array spectrometry, we assessed the DNA methylation of selected stress-response-associated genes (FK506 binding protein 51 [FKBP5], glucocorticoid receptor [NR3C1], corticotropin-releasing hormone receptor 1 [CRHR1]) in isolated immune cells from maternal blood and neonatal umbilical cord blood. In mothers, CM was associated with decreased levels of DNA methylation of FKBP5 and CRHR1 and increased NR3C1 methylation, but not with changes in gene expression profiles. Rs1360780 moderated the FKBP5 epigenetic CM-associated regulation profiles in a gene?×?environment interaction. In newborns, we found no evidence for any intergenerational transmission of CM-related methylation profiles for any of the investigated epigenetic sites. These findings support the hypothesis of a long-lasting impact of CM on the biological epigenetic regulation of stress-response mediators and suggest for the first time that these specific epigenetic patterns might not be directly transmitted to the next generation.

SUBMITTER: Ramo-Fernandez L

PROVIDER: S-EPMC7052131 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The effects of childhood maltreatment on epigenetic regulation of stress-response associated genes: an intergenerational approach.

Ramo-Fernández Laura L Boeck Christina C Koenig Alexandra M AM Schury Katharina K Binder Elisabeth B EB Gündel Harald H Fegert Jöerg M JM Karabatsiakis Alexander A Kolassa Iris-Tatjana IT

Scientific reports 20190418 1

While biological alterations associated with childhood maltreatment (CM) have been found in affected individuals, it remains unknown to what degree these alterations are biologically transmitted to the next generation. We investigated intergenerational effects of maternal CM on DNA methylation and gene expression in N = 113 mother-infant dyads shortly after parturition, additionally accounting for the role of the FKBP5 rs1360780 genotype. Using mass array spectrometry, we assessed the DNA methyl ...[more]

PMID: 31000782

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Project description:BackgroundChildhood maltreatment is associated with adverse health outcomes and this risk can be transmitted to the next generation. We aimed to investigate the association between exposure to maternal childhood maltreatment and common childhood physical and mental health problems, neurodevelopmental disorders, and related comorbidity patterns in offspring.MethodsWe conducted a retrospective cohort study using data from the Environmental influences on Child Health Outcomes (ECHO) Program, which was launched to investigate the influence of early life exposures on child health and development in 69 cohorts across the USA. Eligible mother-child dyads were those with available data on maternal childhood maltreatment exposure and at least one child health outcome measure (autism spectrum disorder, attention-deficit hyperactivity disorder [ADHD], internalising problems, obesity, allergy, and asthma diagnoses). Maternal history of childhood maltreatment was obtained retrospectively from the Adverse Childhood Experiences or Life Stressor Checklist questionnaires. We derived the prevalence of the specified child health outcome measures in offspring across childhood and adolescence by harmonising caregiver reports and other relevant sources (such as medical records) across cohorts. Child internalising symptoms were assessed using the Child Behavior Checklist. Associations between maternal childhood maltreatment and childhood health outcomes were measured using a series of mixed-effects logistic regression models. Covariates included child sex (male or female), race, and ethnicity; maternal and paternal age; maternal education; combined annual household income; maternal diagnosis of depression, asthma, ADHD, allergy, or autism spectrum disorder; and maternal obesity. Two latent class analyses were conducted: to characterise patterns of comorbidity of child health outcomes; and to characterise patterns of co-occurrence of childhood maltreatment subtypes. We then investigated the association between latent class membership and maternal childhood maltreatment and child health outcomes, respectively.FindingsOur sample included 4337 mother-child dyads from 21 longitudinal cohorts (with data collection initiated between 1999 and 2016). Of 3954 mothers in the study, 1742 (44%) had experienced exposure to abuse or neglect during their childhood. After adjustment for confounding, mothers who experienced childhood maltreatment were more likely to have children with internalising problems in the clinical range (odds ratio [OR] 2·70 [95% CI 1·95-3·72], p<0·0001), autism spectrum disorder (1·70 [1·13-2·55], p=0·01), ADHD (2·09 [1·63-2·67], p<0·0001), and asthma (1·54 [1·34-1·77], p<0·0001). In female offspring, maternal childhood maltreatment was associated with a higher prevalence of obesity (1·69 [1·17-2·44], p=0·005). Children of mothers exposed to childhood maltreatment were more likely to exhibit a diagnostic pattern characterised by higher risk for multimorbidity. Exposure to multiple forms of maltreatment across all subtypes of maternal childhood maltreatment was associated with the highest risk increases for most offspring health outcomes, suggesting a dose-response relationship.InterpretationOur findings suggest that maternal childhood maltreatment experiences can be a risk factor for disease susceptibility in offspring across a variety of outcomes and emphasise the need for policies focusing on breaking the intergenerational transmission of adversity.FundingEnvironmental influences on Child Health Outcomes Program, Office of the Director, National Institutes of Health.

Project description:Background:Childhood maltreatment is a strong risk factor for the development of depression in later life. However, the neurobiological mechanisms underlying this vulnerability are not well understood. As depression has been associated with dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and increased responsiveness to psychosocial stressors, we speculated that childhood maltreatment may lead to lasting alteration of the stress response system, thereby increasing the risk of depression. This study investigated the effects of childhood maltreatment on the stress response in healthy subjects while controlling for psychiatric condition. Methods:Forty-eight healthy young adults (24 females) with childhood maltreatment experience and 48 healthy controls (33 females) without such experience were administered the Montreal Imaging Stress Task during functional magnetic resonance imaging. Childhood maltreatment experience was assessed using the 28-item Childhood Trauma Questionnaire (CTQ). Between-group differences in subjective stress levels, whole brain activations and cortisol levels were assessed. Results:Relative to healthy control subjects, individuals exposed to childhood maltreatment exhibited higher subjective stress and cortisol levels. Neurofunctionally, participants with histories of childhood maltreatment displayed significantly increased activation in the dorsolateral prefrontal cortex (dlPFC), insula and precuneus, and decreased activation in ventromedial prefrontal cortex (vmPFC) relative to healthy controls during the psychosocial stress task. Activations in dlPFC and insula correlated with CTQ scores in the childhood maltreatment group. Conclusion:The results of this study show that childhood maltreatment induces lasting changes in brain function and HPA-axis responsiveness to stress. The observed abnormal activation in the dlPFC, insula and vmPFC and enhanced cortisol response are similar to those seen in individuals with depression. This dysfunction might serve as a diathesis that embeds latent vulnerability to psychiatric disorders, and this mechanism provides evidence supporting the stress sensitization model.

Dataset Information

The effects of childhood maltreatment on epigenetic regulation of stress-response associated genes: an intergenerational approach.

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The effects of childhood maltreatment on epigenetic regulation of stress-response associated genes: an intergenerational approach.

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