Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2


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Lower GR-1 F promoter methylation was significantly associated with greater postdexamethasone cortisol suppression. The clustering analysis revealed that maternal and paternal PTSD effects were differentially associated with clinical indicators and GR-1 F promoter methylation.

Epigenetic Biomarkers of Prenatal Maternal Stress

This is the first study to demonstrate alterations of GR-1 F 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.

Offspring of trauma survivors are at increased risk for mental and physical illness 1 — 3. Although studies of the intergenerational transmission of trauma traditionally emphasize the influence of exposure 1 , 2 , there is evidence for the effects of parental trauma-related psychopathology. Parental posttraumatic stress disorder PTSD , but not Holocaust exposure, is associated with alterations in hypothalamic-pituitary-adrenal HPA axis function, including enhanced cortisol suppression following dexamethasone administration 4 and lower baseline cortisol levels 5 , in offspring. These neuroendocrine findings in offspring of trauma survivors are similar to observations in Holocaust survivors and other trauma-exposed persons with PTSD 7.

Transmission of effects from parents to children is thought to be mediated by developmental programming of glucocorticoid signaling 8. Variations in maternal care in rats predict hippocampal glucocorticoid receptor gene expression and levels of cytosine methylation of the exon 1 7 promoter of the rat glucocorticoid receptor gene 9. Studies of postmortem human brain tissue have demonstrated an association between methylation status of the orthologous exon 1F promoter region in the human glucocorticoid receptor gene NR3C1 in the hippocampus and history of childhood abuse This same association between childhood adversity and GR-1 F methylation has been observed in whole blood leukocytes 11 , Although the majority of studies of transgenerational transmission of trauma effects highlight maternal influences, few studies have directly compared maternal and paternal effects on the offspring 1 , 2.

Maternal PTSD has been more strongly associated with lower cortisol levels in Holocaust offspring compared with paternal PTSD 14 , and we recently demonstrated that maternal PTSD is related to increased glucocorticoid receptor sensitivity Inconsistent, over-reactive parenting by mothers predicted lower cortisol variability, whereas a similar parenting style among fathers generally predicted higher cortisol variability in offspring but only in the absence of low maternal cortisol variability.

Similarly, we recently observed that both hour urinary cortisol excretion and cortisol nonsuppression following dexamethasone administration were higher in offspring with paternal PTSD in the absence of maternal PTSD but lower in those with maternal PTSD We further hypothesized that GR-1 F promoter methylation would inversely correlate with glucocorticoid receptor sensitivity. A total of participants were recruited over a 2-year period — , as previously described 15 , and 95 participants completed study procedures.

The study was approved by the institutional review board at the Icahn School of Medicine at Mount Sinai, and written informed consent was obtained. Offspring of Holocaust survivors had to have been born after World War II or after their parents had escaped to safety and have at least one Holocaust survivor parent. Exclusion criteria were any history of psychotic disorder or bipolar illness, significant current alcohol or drug use, and the presence of current PTSD to distinguish the effects of parental PTSD from those associated with expressed PTSD.

Individuals were also excluded if they had a major medical condition or were taking systemic steroids. The Parental PTSD Questionnaire was previously validated against direct clinician assessment of the parent 18 and includes offspring perceptions of the impact of the Holocaust on the offspring. To assess relevant psychiatric symptoms and early-life experiences, participants also completed measures such as the Beck Depression Inventory 19 , the Spielberger State-Trait Anxiety Inventory 20 , the Dissociative Experiences Scale 21 , the Relationship Scales Questionnaire 22 , and the Childhood Trauma Questionnaire 23 , as well as a measure for perceived emotional health Basal morning blood samples were collected for assessment of GR - 1 F promoter methylation and GR-1 F expression and of plasma cortisol levels.

Cytosine methylation was estimated across 39 C—phosphate—G CpG sites in the GR-1 F promoter, using 30 clones per sample, in four batches 10 , The number of methylated clones at each of the 39 CpG sites was converted to a percentage and summed across the GR - 1 F promoter sequence to create a total methylation percentage.

As expected, when methylation in CpG islands is low, the distribution of this variable is positively skewed, and it was transformed natural logarithm for analytic purposes.

The number of CpG sites out of a possible 39 showing methylation in any clone was also determined for each participant. Since peripheral blood mononuclear cell-type composition may affect estimates of DNA methylation 26 , the ratio of lymphocytes to monocytes was calculated peripheral blood mononuclear cell ratio as a proxy of peripheral blood mononuclear cell type and used as a covariate in methylation analyses.

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GR-1 F transcript expression was run as a validation of methylation estimates of the corresponding promoter. For details of the primers and probes used, see Table S1 in the data supplement accompanying the online edition of this article. Data analysis was performed using the qBase v2. Day-1 cortisol levels and day-2 cortisol and dexamethasone levels obtained in association with the low-dose 0. Because a significant percentage of Holocaust offspring indicated no lifetime parental PTSD, non-Holocaust offspring were compared with the Holocaust offspring with no parental PTSD on key demographic and clinical variables see Table S2 in the online data supplement.

Because no relevant differences were observed, participants from both groups were coded as having no maternal or paternal PTSD. To identify effects of parental PTSD, rather than Holocaust exposure, the presence or absence of maternal and paternal Holocaust exposure was included as a covariate. There were no associations of GR-1 F promoter methylation with gender, and including gender as a covariate did not affect any of the analyses. Bonferroni post hoc tests were conducted to investigate significant effects. A correlation between GR-1 F promoter methylation and cortisol decline following dexamethasone administration was performed, partialling out the effects of dexamethasone levels, body mass index, age, smoking history, and peripheral blood mononuclear cell type.

Psychological and clinical data were subject to an unsupervised hierarchical clustering analysis, which allowed phenotypic clustering in relation to maternal and paternal PTSD. Data derived from the clinical rating scales were log 2 transformed, and z-scores were calculated. Contrast was enhanced by ensuring that high numbers reflected more deleterious outcomes. This was followed by a clustering analysis adding GR-1 F promoter percent methylation to determine whether this measure would cluster with any of the identified phenotype-by-group-clusters.

Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2

The data are presented in a heat map that includes dendrograms of the phenotype and group clusters. Two-way analyses of variance ANOVAs were conducted to test the statistical significance of the relationships of the phenotype measures included in the clustering analysis with maternal and paternal PTSD. Demographic and clinical data based on the presence or absence of maternal and paternal PTSD are summarized in Table 1. Seventy-five percent of Holocaust offspring had two Holocaust-exposed parents. PTSD was reported for There were no differences in gender, body mass index, education, or current axis I psychopathology.

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There were differences in lifetime rates of depression and anxiety disorders, such that those without parental PTSD had lower rates of these disorders than those with maternal or paternal PTSD. Given that severe trauma exposure itself may result in epigenetic modifications, a two-way ANCOVA was conducted to investigate the influence of maternal compared with paternal Holocaust exposure status alone on offspring methylation. Results of this ANCOVA, using the same covariates as above, did not reveal any significant main effects of exposure or a significant interaction between maternal and paternal exposure.

The represented data mean, standard deviation are based on an analysis of covariance using raw data. GR-1 F promoter methylation was also associated with the cortisol response to the low-dose dexamethasone suppression test. Offspring with maternal PTSD demonstrated elevations in poor perceived emotional health and depression symptoms and trait anxiety.

Associated Data

Offspring with paternal PTSD only tended to endorse a dismissing, fearful, or insecure attachment style, as well as greater childhood trauma exposure, greater dissociative experiences, and greater sensitivity to violence. The unsupervised hierarchical clustering is presented in dendrograms, with vertical dendrograms representing phenotypic clustering, horizontal dendrograms representing group clustering, and the dendrogram scales represent Euclidean distances. The heat map depicts phenotype-by-group clusters with the color scale based on a phenotype z-score, where blue represents a low score and red represents a high score.

Panel A and panel B contain the same phenotypic variables with the exception of percent methylation in the exon 1 F promoter of the glucocorticoid receptor gene, which is presented only in panel B.

Epigenetics

To provide further interpretability, a series of separate two-way ANOVAs were conducted to determine the relative influence of maternal and paternal PTSD on the clinical indicators included in the clustering analysis Table 2. Maternal and paternal PTSD were associated with different clinical and perceived childhood characteristics. Maternal PTSD was associated with higher self-reported depressive symptoms and trait anxiety and lower perceived emotional health.

Paternal PTSD was associated with higher reports of childhood trauma and less adaptive attachment styles.

Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2 - anveogoto.tk

There were no significant interactions between maternal and paternal PTSD on any of the clinical measures. This is the first study, to our knowledge, to demonstrate alterations of GR-1 F promoter methylation in relation to maternal and paternal PTSD. Although the sample size was limited, findings are consistent with those of previous reports on the effects of parental PTSD on offspring phenotype.

The hierarchical clustering analysis similarly revealed that maternal and paternal PTSD were associated with different offspring psychological characteristics and that lower GR-1 F promoter methylation was specifically associated with maternal PTSD. In this study, phenotypic clustering analysis also demonstrated an association of paternal PTSD, but not maternal PTSD, with childhood abuse and neglect, which is consistent with findings in offspring of male war veterans with PTSD It is notable that the Childhood Trauma Questionnaire assesses a range of potentially traumatic experiences but does not identify the perpetrator.

Thus, it cannot be concluded that fathers with PTSD are more likely than mothers to abuse their children.


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The finding of relatively higher GR-1 F promoter methylation with paternal PTSD in the absence of maternal PTSD is consistent with a previous finding in postmortem human hippocampus of an association between higher GR-1 F promoter methylation and childhood abuse 10 , as well as with more recent findings of an association of higher methylation of specific CpG sites within the GR-1 F promoter in whole blood leukocytes with lower parental care, higher childhood maltreatment, and parental loss in healthy adults 11 and with childhood sexual abuse and extent of childhood maltreatment in individuals with borderline personality disorder The type, severity, chronicity, and developmental stage of adversity, as well as sex of the parent and offspring, may be critical for these associations.

Unfortunately, our sample size was too small to investigate the influence of these factors.

The hypothesis that GR-1 F methylation would be associated with early adversity was based on an interpretation of differences in offspring methylation status on the orthologous promoter region in the rat, based on naturally occurring variations of maternal care 9. The implication of rodent studies of the effect of maternal care on offspring is that early-life challenges, including variations in parental care, are capable of producing enduring epigenetic changes resulting in sustained phenotypic outcomes in the offspring, including altered stress reactivity.

The impact of these effects will depend on context and the degree to which the resulting phenotypic variation meets the particular demands of the prevailing environment. Chronic stress produces variations in the maternal care of the rat i. This increased stress reactivity may be considered adaptive in highly adverse conditions In Holocaust offspring, a parent may have similarly primed his or her offspring for a highly threatening environment that in a post-Holocaust context results in an overgeneralized and exacerbated fear response.

This raises the possibility of indirect effects, such that PTSD in one parent may affect the parenting of the other or create a qualitative shift in the family environment. For example, paternal PTSD has been associated with higher levels of family conflict in this sample It seems that paternal PTSD alone produces effects such as higher cortisol excretion, reduced glucocorticoid receptor sensitivity, and higher GR-1 F promoter methylation, similar to those seen in other samples with major depressive disorder and history of childhood abuse 10 , 32 , It is possible that when both parents are traumatized or express symptoms, there is no buffer for the child, resulting in an unmediated experience of constant or repeated threat imposed by the unpredictability of parental behavior and resulting in the expression of hypervigilance in the offspring.

Because most of the offspring in the present study were raised in the social context of the late s—s, with families structured around traditional gender roles, mothers were more likely to be the primary caregiver, whereas many offspring described fathers who worked long hours and were somewhat distant from the family unit.


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Thus, social context may moderate the processes underlying the intergenerational transmission of trauma While we were able to show different offspring phenotypes based on maternal compared with paternal PTSD, delineations of early parent-child and interparental interactions that may mediate these relationships require further empirical investigation. The functional relevance of the differences in methylation is apparent in the negative correlation between GR-1 F promoter methylation and expression of the respective transcript i.

Furthermore, lower levels of GR-1 F promoter methylation were associated with enhanced glucocorticoid negative feedback inhibition assessed by the dexamethasone suppression test, suggesting that the epigenetic status in blood of offspring resulting from parental PTSD reflects neuroendocrine function. We previously suggested that glucocorticoid receptor sensitivity as assessed by the cortisol response to dexamethasone may be a relatively stable marker of risk in Holocaust offspring 4 , Furthermore, it has previously been suggested that glucocorticoid receptor binding in peripheral tissue peripheral blood mononuclear cells is sufficiently stable to associate with PTSD risk as a trait To our knowledge, there has only been one other study demonstrating an association between GR-1 F promoter methylation and glucocorticoid receptor sensitivity 25 ; however, associations with reduced negative feedback inhibition have been observed in association with higher methylation of specific CpG sites on the GR-1 F promoter A similar moderating effect of maternal PTSD on the effects of paternal PTSD was observed in the same participants examined in the present study with respect to both the cortisol response to dexamethasone and hour urinary cortisol excretion A maternal PTSD effect associated with increased glucocorticoid receptor sensitivity in peripheral tissue was also observed Since DNA methylation is a chemically stable epigenetic mark, these findings suggest that the differences in GR-1 F promoter methylation might mediate the variation in glucocorticoid receptor function and HPA-axis feedback sensitivity that associate with the transgenerational transmitted effects of Holocaust-related psychopathology trauma on the risk for PTSD in the offspring.

The exact mechanisms underlying this transgenerational transmission are unknown. The offspring in this sample were conceived after, and in some cases decades after, parental Holocaust exposure. However, studies with rodents demonstrate that preconception paternal stress can influence behavior and biology in progeny through epigenetic changes in sperm 37 , such that germ-line transmission of epigenetic marks associated with PTSD risk is possible.

Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2 Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2
Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2 Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2
Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2 Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2
Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2 Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2
Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2 Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2
Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2 Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2
Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2 Epigenetics and Neuroendocrinology : Clinical Focus on Psychiatry, Volume 2

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