Influences of Maternal and Paternal PTSD on Epigenetic Regulation of the Glucocorticoid Receptor Gene in Holocaust Survivor Offspring

Abstract

Objective Differential effects of maternal and paternal PTSD have been observed in adult offspring of Holocaust survivors in both glucocorticoid receptor sensitivity and vulnerability to psychiatric disorder. The current study examined the relative influences of maternal and paternal PTSD on DNA methylation of the exon 1F promoter of the glucocorticoid receptor gene (NR3C1) in peripheral blood mononuclear cells (PBMCs), and its relationship to glucocorticoid receptor sensitivity, in Holocaust offspring. Method Adult offspring with at least one Holocaust survivor parent (n=80), and demographically similar participants without parental Holocaust exposure or PTSD (n=15) completed clinical interviews, self-report measures, and biological procedures. Blood samples were collected for analysis of glucocorticoid receptor gene exon 1F (GR-1F) promoter methylation and cortisol levels in response to low-dose dexamethasone, and two-way analysis of covariance was performed using maternal and paternal PTSD as main effects. Hierarchical-clustering analysis was used to permit visualization of maternal vs. paternal PTSD effects on clinical variables. Results A significant interaction demonstrated that in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR-1F promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation. Lower GR-1F promoter methylation was significantly associated with greater post-dexamethasone cortisol suppression. The clustering analysis confirmed that maternal and paternal PTSD effects were differentially associated with clinical indicators. Conclusions This is the first study to demonstrate alterations of GR-1F promoter methylation in relation to parental PTSD and neuroendocrine outcomes. The moderation of paternal PTSD effects by maternal PTSD suggests different mechanisms for the intergenerational transmission of trauma-related vulnerabilities.

Intergenerational Transmission of Stress in Humans

“…Methylation of gene promoter regions typically inhibits gene transcription (Klose and Bird, 2006). Indeed, Holocaust survivor offspring with paternal PTSD exhibited higher NR3C1 promoter methylation, whereas offspring with both maternal and paternal PTSD exhibited lower NR3C1 methylation (Yehuda et al, 2014).…”

Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress

“…Notably, perturbations such as parental stress, malnutrition, infection, or advanced age have been associated with an increased incidence of neurodevelopmental disease in offspring (1), and alterations in their hypothalamic-pituitary-adrenal (HPA) stress axis response may be central to increased disease predisposition (2,3). Studies in diverse animal models have demonstrated similar outcomes, particularly that of offspring HPA axis dysregulation, following either maternal or paternal stress exposure (4-7); yet mechanisms by which parental lifetime stress experience modify offspring development and adult phenotypes remain unclear.…”

Origins of Addiction Predictably Embedded in Childhood Trauma: A Neurobiological Review

“…As one pathway is overloaded from chronic exposure to addictive substances (including behavior) or extreme stress, the other pathway will also become overloaded causing cumulative dysregulation in emotional, behavioral and cognitive domains that cause downstream effect on the ANS and epigenetic translation and intergenerational transfer due to dysregulation of these life-supporting systems. 72) An important question remains as to how intervention and treatment can repair and/or restore the aberrant pathways to normal functioning. Perhaps lessons can be learned from observing patients who are in active and long-term recovery from both CT and addiction, and have seemingly improved the function of RewP and RegP pathways.…”