Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment

Abstract

Epigenetics processes may play a vital role in the biological embedding of early environmental adversity and the development of psychopathology. Accumulating evidence suggests that maltreatment is linked to methylation of the glucocorticoid receptor gene, nuclear receptor subfamily 3, group C, member 1 (NR3C1), which is a key regulator of the hypothalamic–pituitary–adrenal axis. However, prior work has been exclusively cross-sectional, greatly constraining our understanding of stress-related epigenetic processes over time. In the current study, we examined the effect of maltreatment and other adversity on change in NR3C1 methylation among at-risk preschoolers to begin to characterize within-child epigenetic changes during this sensitive developmental period. Participants were 260 preschoolers (3–5 years-old, 53.8% female), including 51.5% with moderate-severe maltreatment in the past six months. Child protection records, semi-structured interviews, and parent reports were used to assess child stress exposure. Methylation of exons 1D and 1F of NR3C1 via saliva DNA were measured at two time points approximately 6 months apart. Results indicate that maltreated children evidence higher baseline levels of NR3C1 methylation, significant decreases in methylation over time, and then at follow-up, lower levels of methylation, relative to non-maltreated preschoolers. Findings from the current study highlight the complex nature of stress related epigenetic processes during early development.

Looking back and moving forward: Evaluating and advancing translation from animal models to human studies of early life stress and DNA methylation

“…Longitudinal studies are a common tool in human developmental studies and could be exploited here to identify both when differences emerge as well as when (and how) they are or can be ameliorated. Indeed, only one paper in this review measured change in DNA methylation (Parent et al, ; saliva sample), and the results are opposite to the interpretation usually made from similar single time point data (decreasing and lower time 2 methylation for the maltreated children vs. non‐maltreated children at NR3C1 exons 1 D and 1 F ). The human studies also nearly entirely lack attempts at intervention, pharmacologically, as is done in animal models, but also behaviorally—despite the literally hundreds of commentaries and reviews that include reference to this possibility (e.g., Heim & Binder, ; Szyf & Bick, , Turecki & Meaney, ).…”

Incorporating epigenetic mechanisms to advance fetal programming theories

“…In the first series of studies that we know of to assess DNA methylation at more than one time point, Parent and colleagues found that maltreated preschoolers exhibited significantly lower levels of DNA methylation of NR3c1 6 months after state agency involvement (Parent et al, 2017). In this same sample, Parade and colleagues found that maltreated children who received more services exhibited increases in FKBP5 methylation in one particular region, which may be related to better regulation of the neuroendocrine stress response system.…”

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

“…However, the epigenetic effect of service utilization was not measured in the children with maltreatment; thus, more studies are needed to conclude the service utilization or other interventions can induce reversal of maltreatment-related epigenetic effects. Child maltreatment is associated with higher initial levels of NR3C1 promoter methylation within six months of documented maltreatment but lower methylation of NR3C1 one year after the maltreatment exposure [105]. This dynamic stress-related DNA methylation changes of NR3C1 reflects the organisms’ early acute response resulting in neurobehavioral dysregulation and later adaptive changes for maintaining high levels of readiness for chronically repeated stressful or unstable conditions [105,106].…”

“…Child maltreatment is associated with higher initial levels of NR3C1 promoter methylation within six months of documented maltreatment but lower methylation of NR3C1 one year after the maltreatment exposure [105]. This dynamic stress-related DNA methylation changes of NR3C1 reflects the organisms’ early acute response resulting in neurobehavioral dysregulation and later adaptive changes for maintaining high levels of readiness for chronically repeated stressful or unstable conditions [105,106]. Overall, these studies demonstrate the potential reversibility of epigenetic processes, although further work is needed to better characterize and demonstrate such phenomenon.…”