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

Abstract

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.

Effect of Early Life Stress on the Epigenetic Profiles in Depression

“…However, this change seemed independent of the cortisol response to stress in those unexposed and mildly or moderately ELS-exposed individuals ( Alexander et al, 2018 ). What is more, one study that enrolled healthy women aged 40 + assumed no significant associations between childhood adversity and DNAm in the NR3C1 promoter but higher DNAm in the ERα shore correlated with higher levels of adversity ( Fiacco et al, 2019 ). In addition, childhood maltreatments and MDD induced different epigenetic changes at the NR3C1 promoter.…”

“…It was only childhood maltreatments, rather than the depressive symptoms, that were associated with reduced NR3C1 expression ( Bustamante et al, 2016 ). Therefore, though most studies supported that ELS increased the NR3C1 DNAm and possibly that the epigenetic alterations resulted in a blunt HPA axis, emerging evidence indicated that even ELS altered NR3C1 DNAm, this molecular change may not be powerful enough to develop depression ( Tyrka et al, 2016 ; Alexander et al, 2018 ; Fiacco et al, 2019 ). It was reported that depressive patients harbored different profiles of the HPA axis, which might be due to a feature of the NR3C1 DNAm ( Malhi and Mann, 2018 ).…”

“…It was reported that depressive patients harbored different profiles of the HPA axis, which might be due to a feature of the NR3C1 DNAm ( Malhi and Mann, 2018 ). Furthermore, demographic characteristics (i.e., age and gender), types and severity of ELS (physical abuse, sexual abuse, emotional abuse, physical and emotional neglects), tissue specificity (i.e., subregions of the brain, blood), dynamic changes in epigenetic profiles (interacting with continuous environment actions), and study design contributed to this discrepancy ( McGowan et al, 2009 ; Perroud et al, 2011 ; Kember et al, 2012 ; Bustamante et al, 2016 ; Cecil et al, 2016 ; Tyrka et al, 2016 ; Alexander et al, 2018 ; Palma-Gudiel et al, 2018 ; Peng et al, 2018 ; Fiacco et al, 2019 ). Besides, because research focusing on the figure of histone modification and non-coding RNA within NR3C1 is lacking, it is unknown whether DNAm, histone modification, and non-coding RNA coordinate or disintegrate with each other.…”

Differential ESR1 Promoter Methylation in the Peripheral Blood—Findings from the Women 40+ Healthy Aging Study

“…Women aged 40-75 years were recruited in the context of the Women 40+ Healthy Aging Study, a larger cross-sectional investigation including healthy middle-aged and older women [72][73][74]. To be included in the study, women had to report good, very good, or excellent health.…”

The Swiss Perimenopause Study – study protocol of a longitudinal prospective study in perimenopausal women

“…For epigenetic analyses, we perform a bisulfite conversion of DNA using the EZ 96-DNA Methylation-Gold Kit (Zymo Research, Luzern, Switzerland). The procedure for the next-generation sequencing (NGS) library preparation is described elsewhere by our research group [80].…”