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| Name | Class |
|---|---|
| University Hospital Tuebingen | OTHER |
| Uppsala University | OTHER |
| German Research Foundation | OTHER |
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Pubertal transition leads to enduring neuroendocrine changes along with changes in the epigenome. The prevalence of psychiatric disorders significantly increases in females compared to males after puberty. There is likely to be an interaction between epigenetics, hormones and neurophysiological processes during puberty, leading to the increased prevalence of mental disorders in females. This study aims to shed light on these interactions underlying the emerging sex differences after puberty. Specifically, it seeks to investigate the epigenetic modifications and subsequent changes in gene expression during the pubertal transition and their association with negative emotionality (e.g., acute stress response and depressive symptoms) at molecular, neuronal, subjective and physiological levels.
In order to investigate epigenetic and neuroimaging correlates of negative emotionality in pubertal girls, the study employs a cross-sectional design, enrolling 50 pre-pubescent girls (8-10 years) and 50 post-pubescent girls (15-17 years) as healthy participants. Comprehensive data will be collected using self- and parent-report questionnaires on pubertal status, prenatal complications, adverse life events, stress and coping mechanisms, mood and anxiety symptoms, gender identity, and reproductive health. To delve into the neuronal correlates of stress, participants will undergo (f)MRI and MIST. Additionally, physiological stress responses will be assessed through heart rate and skin conductance measurements. Participants will provide blood, saliva, and hair samples for hormone, methylation and expression analysis. DNA methylation analysis will be performed on whole blood and saliva samples using pyrosequencing, focusing on genes that are responsive to estrogen and genes involved in estrogen signaling, based on the previous literature reporting an overrepresentation of estrogen-responsive genes among the differentially methylated sites across the entire genome in girls during puberty. The effects of methylation on gene expression will be measured using reverse transcription real-time PCR. Cortisol levels will be assessed from saliva collected six times during MIST to evaluate the acute stress response and from hair to assess chronic stress. Sex steroids such as estrogen and progesterone from blood will be analyzed using LC-MS/MS. The study aims to provide insights into the intricate relationship between epigenetic modifications, gene expression and negative emotionality (e.g., stress reactivity and internalizing symptoms) during puberty in girls.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pre-pubertal girls (children) | 8-10 years of girls having pubertal stage 1 |
| |
| Post-pubertal girls (adolescents) | 15-17 years of girls having pubertal stage 5 |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Stress | Behavioral | Montreal Imaging Stress Task is a stress paradigm in the scanner to examine neuronal correlates of acute psychosocial stress. |
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| Measure | Description | Time Frame |
|---|---|---|
| DNA methylation differences between pre- and post-pubertal girls in candidate genes | DNA methylation (DNAm) leves in genes involved in estrogen signaling and neuronal estrogen responsive genes in blood and saliva | Measured once after MRI measurement (approximately 30 minutes). |
| Correlation between DNA methylation and neuronal activity during acute stress | Neuronal activity during acute stress is determined by the contrast differences between stress and control conditions assessed with task-based fMRI, Montreal Imaging Stress Task (MIST). The correlation between neuronal activity and DNA methylation. Comparing pre- and post-pubescent girls. | Measured once: 3 runs of MIST lasting 20 minutes in total. |
| The mediating role of sex steroids in DNA methlation and negative emotionality | The mediating effect of estradiol, progesterone, testosterone and allopregnanolone levels in blood on the correlation between DNA methylation and indicators of negative emotionality (e.g., neuronal activity during stress (MIST task) and mood symptoms). Comparing pre- and post-pubescent girls | Measured once for each part: 20 minutes for MIST, 30 minutes for blood and saliva collection, and 1 hour for questionnaires |
| Measure | Description | Time Frame |
|---|---|---|
| Correlation between DNA methylation and gene expression in candidate genes | The expression levels of genes involved in estrogen signaling and neuronal estrogen responsive genes in blood and saliva with RT-PCR. Correlation between DNA methlaytion and expression. | Measured once after MRI measurement (approximately 30 minutes) |
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Inclusion Criteria:
Exclusion Criteria:
Additional exclusion criteria for MRI:
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Pubescent girls between 8 and 17 years of age living and schooling in Tübingen and surrounding area
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Vanessa Nieratschker, Prof. Dr. | Contact | +497071-2985523 | vanessa.nieratschker@med.uni-tuebingen.de | |
| Birgit Derntl, Prof. Dr. | Contact | +497071 29-85437 | birgit.derntl@med.uni-tuebingen.de |
| Name | Affiliation | Role |
|---|---|---|
| Vanessa Nieratschker, Prof. | University Hospital Tuebingen | Principal Investigator |
| Mirac Nur Musaoglu, MD | University Hospital Tuebingen | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Tuebingen; Department of Psychiatry & Psychotherapy; Tuebingen | Recruiting | Tübingen | Baden-Wurttemberg | 72076 | Germany |
After the publication of the key results of the study, all anonymized imaging data will be made publicly available.
Data will become available after an embargo period of 12 months after completion of the study.
Until the data is publicly available, researchers may contact the lead PI to gain access.
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Blood, saliva and hair
| Correlation between DNA methylation and HPA-axis response |
Cortisol levels from saliva samples collected before and after MIST. Correlation between area under the curve (AUC) for cortisol and DNA methylation. Is there a mediating role of DNA methylation on the correlation between HPA-axis reactivity and negative emotionality (e.g., internalizing symptoms and stress processing)? Comparing pre- and post-pubescent girls. |
| Measured six times: 1 hour before MIST(1), just before(1) and after(1) MIST, and three times more in 20-minute intervals after MIST. Each saliva collection lasts approx. 2 minutes. |
| Correlation between DNA methylation and subjective stress response | Correlation between emotional ratings and stress levels assessed with each saliva sample before and after MIST and DNA methylation. Emotional ratings are based on self-assessment mannikin (SAM) which is a non-verbal pictorial tool. Stress levels evaluated with a stress thermometer using a scale of 1-10; 1 indicating not at all, 10 very strong. Is there a mediating effect of DNA methylation on the correlation between subjective stress response and negative emotionality (e.g., internalizing symptoms and stress processing). Comparing pre-and post-pubertal girls | Measured six times: 1 hour before MIST(1), just before(1) and after(1) MIST, and three times more in 20-minute intervals after MIST. Each rating takes approx. 10 minutes. |
| Correlation between DNA methylation and phsiological stress response | Correlation between HR, HRV and skin conductance changes during stress task (MIST) and DNA methylation. The interaction between physiological acute stress response and DNA methylation in relation to negative emotionality (e.g., internalizing symptoms and stress processing). Comparing pre-and post-pubertal girls | Measured once: 20 minutes for phsiological data during MRI measurement |
| Correlation between DNA methylation and functional connectivity | The correlation between functional connectivity in brain networks (e.g., default mode network (DMN) and salience network (SN)) and DNA methlaytion. The correlation between regions of interest (i.e., amygdala, anterior cingulate cortex, and hippocampus) activity during rest condition and DNA methylation. Is there a mediating role of DNA methylation on the correlation between resting-state neuronal activity and negative emotionality (e.g., mood and anxiety symptoms)? Comparing pre- and post-pubertal girls. | Measured once with resting-state functional MRI, approximately 10 mintes |
| Correlation between DNA methylation and brain gray matter structure | The correlation between gray matter volumes obtained from anatomical T1-weighted images in regions of interest (i.e., amygdala, dorsolateral prefrontal cortex, putamen, anterior cingulate, hippocampus, ventral striatum) and DNA methylation. Is there a mediating role of DNA methylation on the correlation between region of interest gray matter volumes and negative emotionality (e.g., stress processing, mood and anxiety symptoms). Comparing pre- and post-pubescent girls. | Measured once with MPRAGE MRI, approximately 10 minutes. Analyzed and reported over the course of the study, in average of 1 year |