Negative Emotionality in Relation to Epigenetics of Estrogen Signaling During Puberty
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- DNA methylation differences between pre- and post-pubertal girls in candidate genes
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 8 Years 至 17 Years（Child）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •healthy girls
- •aged between 8-10 and having pubertal stage 1 or between 15-17 and having pubertal stage 5
- •normal body mass index according to age (between 5th and 85th percentile)
- •non-smoking
- •German language fluency
- •Attending age-appropriate schools
排除标准
- •neurological or psychiatric disease
- •medical problems such as hormonal, metabolic, developmental or chronic diseases (e.g., congenital disorders, precocious puberty, polycystic ovarian syndrome, diabetes or congestive heart failure)
- •any kind of hormonal, pharmacological or psychotropic treatment in the last three months
- •engaging in competitive/extreme sports
- •Additional exclusion criteria for MRI:
- •People with non-removable metal objects on or in the body
- •Tattoos (if not MRI-incompatible according to expert guidelines)
- •Pathological hearing or increased sensitivity to loud noises
- •Claustrophobia
- •Surgery less than three months ago
- •Moderate or severe head injury
结局指标
主要结局
DNA methylation differences between pre- and post-pubertal girls in candidate genes
时间窗: Measured once after MRI measurement (approximately 30 minutes).
DNA methylation (DNAm) leves in genes involved in estrogen signaling and neuronal estrogen responsive genes in blood and saliva
Correlation between DNA methylation and neuronal activity during acute stress
时间窗: Measured once: 3 runs of MIST lasting 20 minutes in total.
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.
The mediating role of sex steroids in DNA methlation and negative emotionality
时间窗: Measured once for each part: 20 minutes for MIST, 30 minutes for blood and saliva collection, and 1 hour for questionnaires
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
次要结局
- Correlation between DNA methylation and gene expression in candidate genes(Measured once after MRI measurement (approximately 30 minutes))
- Correlation between DNA methylation and HPA-axis response(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(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(Measured once: 20 minutes for phsiological data during MRI measurement)
- Correlation between DNA methylation and functional connectivity(Measured once with resting-state functional MRI, approximately 10 mintes)
- Correlation between DNA methylation and brain gray matter structure(Measured once with MPRAGE MRI, approximately 10 minutes. Analyzed and reported over the course of the study, in average of 1 year)