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Altered Stress-Induced Regulation of Genes in Monocytes in Adults with a History of Childhood Adversity.

ABSTRACT: Exposure to serious or traumatic events early in life can lead to persistent alterations in physiological stress response systems, including enhanced cross talk between the neuroendocrine and immune system. These programming effects may be mechanistically involved in mediating the effects of adverse childhood experience on disease risk in adulthood. We investigated hormonal and genome-wide mRNA expression responses in monocytes to acute stress exposure, in a sample of healthy adults (n=30) with a history of early childhood adversity, and a control group (n=30) without trauma experience. The early adversity group showed altered hypothalamus-pituitary-adrenal axis responses to stress, evidenced by lower ACTH and cortisol responses. Analyses of gene expression patterns showed that stress-responsive transcripts were enriched for genes involved in cytokine activity, cytokine-cytokine receptor interaction, chemokine activity, and G-protein coupled receptor binding. Differences between groups in stress-induced regulation of gene transcription were observed for genes involved in steroid binding, hormone activity, and G-protein coupled receptor binding. Transcription factor binding motif analysis showed an increased activity of pro-inflammatory upstream signaling in the early adversity group. We also identified transcripts that were differentially correlated with stress-induced cortisol increases between the groups, enriched for genes involved in cytokine-cytokine receptor interaction and glutamate receptor signaling. We suggest that childhood adversity leads to persistent alterations in transcriptional control of stress-responsive pathways, which-when chronically or repeatedly activated-might predispose individuals to stress-related psychopathology.

SUBMITTER: Schwaiger M

PROVIDER: S-EPMC4987852 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Altered Stress-Induced Regulation of Genes in Monocytes in Adults with a History of Childhood Adversity.

Schwaiger Marion M Grinberg Marianna M Moser Dirk D Zang Johannes C S JC Heinrichs Markus M Hengstler Jan G JG Rahnenführer Jörg J Cole Steve S Kumsta Robert R

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20160419 10

Exposure to serious or traumatic events early in life can lead to persistent alterations in physiological stress response systems, including enhanced cross talk between the neuroendocrine and immune system. These programming effects may be mechanistically involved in mediating the effects of adverse childhood experience on disease risk in adulthood. We investigated hormonal and genome-wide mRNA expression responses in monocytes to acute stress exposure, in a sample of healthy adults (n=30) with ...[more]

PMID: 27091381

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Project description: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 (ER?) upon early life adversity. We investigated the association of type and severity of childhood adversity with methylation in NR3C1 and ER? and additionally considered associations between methylation and steroid hormone secretion. Methods: The percentage of methylation within the NR3C1 promoter and the ER? 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 ER? shore than those who did not (p = .001). Additionally, higher levels of adversity were associated with higher levels of ER? 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 ER? 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.

Project description:BACKGROUND:Adverse childhood experiences (ACEs), such as abuse or chronic stress, program an exaggerated adult inflammatory response to stress. Emerging rodent research suggests that the gut microbiome may be a key mediator in the association between early life stress and dysregulated glucocorticoid-immune response. However, ACE impact on inflammatory response to stress, or on the gut microbiome, have not been studied in human pregnancy, when inflammation increases risk of poor outcomes. The aim of this study was to assess the relationships among ACE, the gut microbiome, and cytokine response to stress in pregnant women. METHODS:Physically and psychiatrically healthy adult pregnant women completed the Adverse Childhood Experiences Questionnaire (ACE-Q) and gave a single stool sample between 20 and 26?weeks gestation. Stool DNA was isolated and 16S sequencing was performed. Three 24-hour food recalls were administered to assess dietary nutrient intake. A subset of women completed the Trier Social Stress Test (TSST) at 22-34?weeks gestation; plasma interleukin-6 (IL-6), interleukin-1? (IL-1?), high sensitivity C-reactive protein (hsCRP), tumor necrosis factor ? (TNF-?), and cortisol were measured at four timepoints pre and post stressor, and area under the curve (AUC) was calculated. RESULTS:Forty-eight women completed the ACE-Q and provided stool; 19 women completed the TSST. Women reporting 2 or more ACEs (high ACE) had greater differential abundance of gut Prevotella than low ACE participants (q?=?5.7?×?10^-13). Abundance of several gut taxa were significantly associated with cortisol, IL-6, TNF-? and CRP AUCs regardless of ACE status. IL-6 response to stress was buffered among high ACE women with high intake of docosahexaenoic acid (DHA) (p?=?0.03) and eicosapentaenoic acid (EPA) (p?=?0.05). DISCUSSION:Our findings suggest that multiple childhood adversities are associated with changes in gut microbiota composition during pregnancy, and such changes may contribute to altered inflammatory and glucocorticoid response to stress. While preliminary, this is the first study to demonstrate an association between gut microbiota and acute glucocorticoid-immune response to stress in a clinical sample. Finally, exploratory analyses suggested that high ACE women with high dietary intake of ?-3 polyunsaturated fatty acids (PUFAs) had a dampened inflammatory response to acute stress, suggesting potentially protective effects of ?-3s in this high-risk population. Given the adverse effects of inflammation on pregnancy and the developing fetus, mechanisms by which childhood adversity influence the gut-brain axis and potential protective factors such as diet should be further explored.

Dataset Information

Altered Stress-Induced Regulation of Genes in Monocytes in Adults with a History of Childhood Adversity.

Publications

Altered Stress-Induced Regulation of Genes in Monocytes in Adults with a History of Childhood Adversity.

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