Child maltreatment and NR3C1 exon 1F methylation, link with deregulated hypothalamus-pituitary-adrenal axis and psychopathology: A systematic review

Wadji, Dany Laure; Tandon, Tanya; Wanda, Germain Jean Magloire Ketcha; Wicky, Chantal; Dentz, Amélie; Hasler, Gregor; Morina, Naser; Martin‐Soelch, Chantal

doi:10.1016/j.chiabu.2021.105304

Cited by 23 publications

(16 citation statements)

References 42 publications

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“…We analyzed a total of 6 genes: ESR1, DRD2, LINE1, MST1R, that we have previously demonstrated to be differentially methylated in prostate and breast cancers [42][43][44]. We have included in this study 2 new methylated assays; NR3C1 and FKBP5 which have been reported to demonstrated differential methylation in response to stress and violence [45][46][47]. These genes were selected based on their potential role in immune signaling, sex steroidal signaling pathways and neurotransmission.…”

Section: Resultsmentioning

confidence: 99%

Sex differences in saliva-based DNA methylation changes and environmental stressor in young African American adults

et al. 2022

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Background Low socioeconomic status neighborhood exposure to stress and violence may be sources of negative stimuli that poses significant health risks for children, adolescents and throughout the life course of an individual. The study aims to investigate if aberrant epigenetic DNA methylation changes may be a potential mechanism for regulating neighborhood exposures and health outcomes. Methods Exposure to environmental stressors identified in 98 young African American (AA) adults aged 18–25 years old from the Washington D.C., area were used in the study. We correlated the association between stress markers; cortisol, CRP, IgG, IGA, IgM, and self-reported exposure to violence and stress, with quantitative DNA methylation changes in a panel of gene-specific loci using saliva DNA. Results In all participants studied, the exposure to violence was significant and negatively correlated with DNA methylation of MST1R loci (p = 0.032; r = -0.971) and nominally significant with NR3C1 loci (p = 0.053; r = -0.948). In addition, we observed significant and negative correlation of DNA methylation changes of LINE1 (p = 0.044; r = -0.248); NR3C1 (p = 0.017; r = -0.186); MSTR1 (p = 0.022; r = -0.192); and DRD2 (p = 0.056; r = -0.184; albeit nominal significant correlation) with IgA expression. On the other hand, we observed a significant and position correlation of DNA methylation changes in DRD2 (p = 0.037; r = 0.184) with IgG expression. When participants were stratified by sex, we observed in AA young male adults, significant DNA methylation changes of MST1R (p< 0.05) and association with exposure to violence and IgG level. We also observed significant DNA methylation levels of DRD2 (p< 0.05) and association with IgA, IgG, and cortisol level. Furthermore, we observed significant DNA methylation changes of NR3C1 (p< 0.05) with stress, IgA, and IgG in the male participants only. On the other hand, we only observed significant and a positive association of IgG with DNA methylation levels of ESR1 (p = 0.041) in the young AA female participants. Conclusion Our preliminary observation of significant DNA methylation changes in neuronal and immune genes in saliva samples supports our recently published genome-wide DNA methylations changes in blood samples from young AA male adults indicating that saliva offers a non-invasive means for DNA methylation prediction of exposure to environmental stressors in a gender-specific manner.

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Section: Resultsmentioning

confidence: 99%

Sex differences in saliva-based DNA methylation changes and environmental stressor in young African American adults

et al. 2022

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“…For example, within the Avon Longitudinal Study of Parents And Children, exposure to childhood adversities before 7 years of age was associated with differential methylation of 38 CpG sites among children at 7 years of age; most loci differences (n=35) were predicted by exposure to childhood adversities before 3 years of age. 22 Specific gene methylation has been identified between stressors and the neuron-specific glucocorti-coid receptor, 23 notably among studies examining child maltreatment and NR3C1 gene methylation 24 ; however, other studies have not been able to replicate these findings in epigenome-wide associations. 25 In addition, there is a lack of evidence linking neuron-specific glucocorticoid receptor methylation to cardiometabolic risk.…”

Section: Considerations For Clinical Practicementioning

confidence: 99%

Next Generation, Modifiable Cardiometabolic Biomarkers: Mitochondrial Adaptation and Metabolic Resilience: A Scientific Statement From the American Heart Association

Mietus-Snyder,

Perak,

Cheng

et al. 2023

Circulation

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Cardiometabolic risk is increasing in prevalence across the life span with disproportionate ramifications for youth at socioeconomic disadvantage. Established risk factors and associated disease progression are harder to reverse as they become entrenched over time; if current trends are unchecked, the consequences for individual and societal wellness will become untenable. Interrelated root causes of ectopic adiposity and insulin resistance are understood but identified late in the trajectory of systemic metabolic dysregulation when traditional cardiometabolic risk factors cross current diagnostic thresholds of disease. Thus, children at cardiometabolic risk are often exposed to suboptimal metabolism over years before they present with clinical symptoms, at which point life-long reliance on pharmacotherapy may only mitigate but not reverse the risk. Leading-edge indicators are needed to detect the earliest departure from healthy metabolism, so that targeted, primordial, and primary prevention of cardiometabolic risk is possible. Better understanding of biomarkers that reflect the earliest transitions to dysmetabolism, beginning in utero, ideally biomarkers that are also mechanistic/causal and modifiable, is critically needed. This scientific statement explores emerging biomarkers of cardiometabolic risk across rapidly evolving and interrelated “omic” fields of research (the epigenome, microbiome, metabolome, lipidome, and inflammasome). Connections in each domain to mitochondrial function are identified that may mediate the favorable responses of each of the omic biomarkers featured to a heart-healthy lifestyle, notably to nutritional interventions. Fuller implementation of evidence-based nutrition must address environmental and socioeconomic disparities that can either facilitate or impede response to therapy.

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“…To date, human studies have predominately focused on the effects of severely disrupted caregiving (i.e., child maltreatment) on DNA methylation and provide some preliminary evidence that NR3C1 hypermethylation may link an adverse caregiving environment to later psychopathology (for a review see Wadji et al, 2021). However, relatively little attention has been given to typical variation in caregiving within community samples.…”

Section: Introductionmentioning

confidence: 99%

Maternal sensitivity and child internalizing and externalizing behavior: a mediating role for glucocorticoid receptor gene (NR3C1) methylation?

et al. 2023

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The early caregiving environment can have lasting effects on child mental health. Animal models suggest that glucocorticoid receptor gene (NR3C1) DNA methylation plays a mediating role in linking more responsive caregiving to improved behavioral outcomes by its impact on the stress regulatory system. In this longitudinal study, we examined whether children’s NR3C1 methylation levels mediate an effect of maternal sensitivity in infancy on levels of child internalizing and externalizing behavior in a community sample. Maternal sensitivity of 145 mothers was rated at infant age 5 weeks, 12 months, and 30 months by observing mother–infant interactions. Buccal DNA methylation was assessed in the same children at age 6 years and maternal-reported internalizing and externalizing behavior was assessed at age 6 and 10 years. Higher sensitivity at age 5 weeks significantly predicted lower DNA methylation levels at two NR3C1 CpG loci, although methylation levels at these loci did not mediate an effect of maternal sensitivity on levels of child internalizing and externalizing behavior. Overall, the study provides evidence that maternal sensitivity in early infancy is associated with DNA methylation levels at loci involved in stress regulation, but the significance of this finding for child mental health remains unclear.

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Child maltreatment and NR3C1 exon 1F methylation, link with deregulated hypothalamus-pituitary-adrenal axis and psychopathology: A systematic review

Cited by 23 publications

References 42 publications

Sex differences in saliva-based DNA methylation changes and environmental stressor in young African American adults

Sex differences in saliva-based DNA methylation changes and environmental stressor in young African American adults

Next Generation, Modifiable Cardiometabolic Biomarkers: Mitochondrial Adaptation and Metabolic Resilience: A Scientific Statement From the American Heart Association

Maternal sensitivity and child internalizing and externalizing behavior: a mediating role for glucocorticoid receptor gene (NR3C1) methylation?

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