Childhood Abuse, Promoter Methylation of Leukocyte
            <i>NR3C1</i>
            and the Potential Modifying Effect of Emotional Support

Shields, Alexandra E.; Wise, Lauren A.; Ruiz-Narváez, Edward A.; Seddighzadeh, Bobak; Byun, Hyang-Min; Cozier, Yvette C.; Rosenberg, Lynn; Palmer, Julie R.; Baccarelli, Andrea A.

doi:10.2217/epi-2016-0074

Cited by 50 publications

(35 citation statements)

References 53 publications

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“…This study had a number of limitations, the major one being the assessment of NR3C1 methylation using DNA from a peripheral tissue (saliva DNA). Still, previous studies on NR3C1 exon 1F methylation and early trauma have generated similar results by utilizing DNA from brain 10 , 11 , saliva 12 , 18 , 28 , and whole blood leukocytes 13 , 14 , 16 , 22 . In addition, the cross-sectional design prevented the study of the timing of methylation in relation to the timing of the stressful events and of the onset of symptoms.…”

Section: Discussionmentioning

confidence: 69%

NR3C1 hypermethylation in depressed and bullied adolescents

et al. 2018

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The disruption of key epigenetic processes during critical periods of brain development can increase an individual’s vulnerability to psychopathology later in life. For instance, DNA methylation in the glucocorticoid receptor gene (NR3C1) in adulthood is known to be associated with early-life adversities and has been suggested to mediate the development of stress-related disorders. However, the association between NR3C1 methylation and the emergence of internalizing symptoms in childhood and adolescence has not been studied extensively. In the present report, we used saliva DNA from a cohort of Swedish adolescents (13–14 years old; N = 1149) to measure NR3C1 methylation in the exon 1F region. Internalizing psychopathological symptoms were assessed using the Center for Epidemiologic Studies Depression Scale for Children (CES-DC). We found that NR3C1 hypermethylation was cross-sectionally associated with high score for internalizing symptoms in the whole group as well as among the female participants. In addition, an analysis of social environmental stressors revealed that reports of bullied or lacking friends were significantly associated with NR3C1 hypermethylation. This cross-sectional association of NR3C1 exon 1F hypermethylation with internalizing psychopathology in adolescents, as well as with bullying and lack of friends are novel results in this field. Longitudinal studies are needed to address whether NR3C1 methylation mediates the link between social stressors and psychopathology in adolescence.

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Section: Discussionmentioning

confidence: 69%

NR3C1 hypermethylation in depressed and bullied adolescents

et al. 2018

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“…Additionally, our study evaluated associations with telomere length as a marker of accelerated aging, but other markers including DNA methylation, are important and their examination will enhance our understanding of the biological impact of abuse experienced in early-life [ 68 ]. Our group has previously shown that childhood abuse victimization was associated with hypermethlation in NR3C1 [ 39 ]. Ongoing analyses within the Study on Psychosocial Stress, Spirituality, and Health are examining the impact of abuse and other stressful life experiences on DNA methylation within candidate genes in the stress pathway ( HSD11B1 , HSD11B2 , NR3C1 , FKBP5 ) and in epigenome-wide association studies.…”

Section: Discussionmentioning

confidence: 99%

“…We assigned respondents 1 point for each report of a physical abuse item that occurred >4 times, except for “choked or burned” or “seriously harmed someone I loved” where we assigned 1 point if they occurred 1 to 3 times and 2 points if they occurred 4 times. The resulting scores were categorized using the following groupings: no abuse (0), mild abuse (1), moderate abuse (2), severe abuse (≥3) [ 39 ]. We evaluated the impact of physical abuse in childhood or adolescence separately, and cross-classified yes/no indicators of physical abuse in childhood and adolescence to generate a four-level variable that indicated no physical abuse, physical abuse in childhood only, adolescence only, or childhood and adolescence.…”

Section: Methodsmentioning

confidence: 99%

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Physical and sexual abuse in childhood and adolescence and leukocyte telomere length: A pooled analysis of the study on psychosocial stress, spirituality, and health

Warner

Zhang

et al. 2020

PLoS ONE

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Introduction We examined whether abuse in childhood and/or adolescence was associated with shorter telomere length in a pooled analysis of 3,232 participants from five diverse cohorts. We also assessed whether religion or spirituality (R/S) could buffer deleterious effects of abuse. Methods Physical and sexual abuse in childhood (age <12) and adolescence (age 12–18) was assessed using the Revised Conflict Tactics Scale and questions from a 1995 Gallup survey. We measured relative leukocyte telomere lengths (RTL) using quantitative real time polymerase chain reaction. We used generalized estimating equations to assess associations of physical and sexual abuse with log-transformed RTL z-scores. Analyses were conducted in each cohort, overall, and stratified by extent of religiosity or spirituality and religious coping in adulthood. We pooled study‐specific estimates using random‐effects models and assessed between-study heterogeneity. Results Compared to no abuse, severe sexual abuse was associated with lower RTL z-scores, in childhood: -15.6%, 95% CI: -25.9, -4.9; p-trend = 0.04; p-heterogeneity = 0.58 and in adolescence: -16.5%, 95% CI: -28.1, -3.0; p-trend = 0.08; p-heterogeneity = 0.68. Sexual abuse experienced in both childhood and adolescence was associated with 11.3% lower RTL z-scores after adjustment for childhood and demographic covariates (95% CI: -20.5%, -2.0%; p-trend = 0.03; p-heterogeneity = 0.62). There was no evidence of effect modification by R/S. Physical abuse was not associated with telomere length. Conclusions Sexual abuse in childhood or adolescence was associated with a marker of accelerated biological aging, decreased telomere length. The lack of moderation by R/S may be due to inability to capture the appropriate time period for those beliefs and practices.

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“…Therefore, the few studies in healthy adults with a history of childhood adversity are especially valuable for detecting whether methylation in NR3C1 is responsive to early life adversity. In such adults, greater childhood adversity was associated with higher methylation in NR3C1 (32, 33). These findings suggest that early life adversity might pose a significant independent risk factor for NR3C1 methylation.…”

Section: Introductionmentioning

confidence: 98%

DNA Methylation in Healthy Older Adults With a History of Childhood Adversity—Findings From the Women 40+ Healthy Aging Study

et al. 2019

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Background: Adversity in early development seems to increase the risk of stress-related somatic disorders later in life. Physiologically, functioning of the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes is often discussed as long-term mediators of risk. In particular, DNA methylation in the glucocorticoid receptor gene promoter (NR3C1) has been associated with type and strength of early life adversity and subsequent effects on HPA axis signaling in humans. Animal studies, moreover, suggest changes in DNA methylation in the estrogen receptor gene (ERα) upon early life adversity. We investigated the association of type and severity of childhood adversity with methylation in NR3C1 and ERα and additionally considered associations between methylation and steroid hormone secretion. Methods: The percentage of methylation within the NR3C1 promoter and the ERα shore was investigated using dried blood spot samples of 103 healthy women aged 40–73 years. Childhood adversity was examined with the Childhood Trauma Questionnaire. Linear regression analyses were performed with methylation as dependent variable and the experience of emotional abuse and neglect, physical abuse and neglect, and sexual abuse (compared to non-experience) as independent variables. All analyses were controlled for age, BMI, annual household income, and smoking status and were adjusted for multiple testing. Results: Overall, over 70% of the sample reported having experienced any kind of abuse or neglect of at least low intensity. There were no significant associations between childhood adversity and methylation in the NR3C1 promoter (all p > .10). Participants reporting emotional abuse showed significantly higher methylation in the ERα shore than those who did not (p = .001). Additionally, higher levels of adversity were associated with higher levels of ERα shore methylation (p = .001). Conclusion: In healthy women, early life adversity does not seem to result in NR3C1 promoter hypermethylation in midlife and older age. This is the first study in humans to suggest that childhood adversity might, however, epigenetically modify the ERα shore. Further studies are needed to gain a better understanding of why some individuals remain healthy and others develop psychopathologies in the face of childhood adversity.

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Childhood Abuse, Promoter Methylation of Leukocyte NR3C1 and the Potential Modifying Effect of Emotional Support

Cited by 50 publications

References 53 publications

NR3C1 hypermethylation in depressed and bullied adolescents

NR3C1 hypermethylation in depressed and bullied adolescents

Physical and sexual abuse in childhood and adolescence and leukocyte telomere length: A pooled analysis of the study on psychosocial stress, spirituality, and health

DNA Methylation in Healthy Older Adults With a History of Childhood Adversity—Findings From the Women 40+ Healthy Aging Study

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