Epigenetic susceptibility of behavioral and addictive disorders during pre/pubescence after natural disaster exposures in-utero

摘要/摘要：未来精神和成瘾障碍的风险始于生命早期， 强调宫内环境的关键作用的证据。母亲的心理社会压力有 对产前环境产生重大影响，并导致不良的健康和神经行为结果 后代。我们的研究(孕期应激，SIP研究)以及其他人的研究表明，在子宫中暴露 母亲的心理社会压力是恐惧相关和冲动控制相关问题风险的主要预测因素 在童年早期。我们现在已经做好了准备，可以对我们独特的种族和 资金多元化的SIP研究人群，以确定儿童行为和生理反应的生物标记物 与未来随后的行为障碍和成瘾风险相关。尽管它很重要，但很少有研究 研究从胎盘早期到青春期前/青春期的胎盘分子特征和生物行为评估 相位。利用SIP研究的生物资源库和深层表型儿童行为，我们的初步结果显示 下丘脑-垂体-肾上腺(HPA)轴和免疫系统的表观遗传学变化与 暴露在宫内母体压力下的儿童的恐惧、焦虑和情绪失调。SIP研究队列 有许多优势：其始终如一的长期跟踪，从子宫内，其多样性(经济和种族)，其 储存生物标本(胎盘、脚趾甲、毛发样本)的广泛储存库及其准实验设计。 这群人现在正进入青春期前(9-13岁)，这是一个快速社会和生物转型的时期，也是一个高峰期。 对于适应不良、冒险行为的出现，大脑仍在发育认知功能。vbl.使用 这个无与伦比的机会，我们将跟随队列1)检查子宫内暴露于SS的作用，以及 出生后压力(正常压力、父母教养方式)对神经发育功能的影响 多项行为、生理和神经心理评估；2)确定 胎盘中的产前表观基因组特征(以及对HPA轴和免疫网络的先验关注) 基因)对随后的负面行为特征(即过度焦虑和破坏性)的风险 行为)和执行功能受损，已知会增加早期开始使用药物的风险。 在我们之前的工作之后，我们还将检查行为表型的性别特定表现(更多 将问题内化于女孩，外化于男孩)。我们将进一步探讨金融市场的调节作用。 出生前和产后应激交叉时的社会经济状况对个体差异的影响 认知神经行为，使青春期前/青春期儿童更容易发生随后的 行为和成瘾障碍。我们将建立我们独一无二的储存生物标本和配置文件的存储库 染色质在胎盘的表观基因组和RNA表达网络中的可及性。考虑到陡峭的 不利应激源，特别是自然灾害(如飓风、野火和流行病)的发生率增加， 生长抑素应激对胎儿宫内神经发育的短期和长期影响 青春期前/青春期，将帮助我们识别问题，并可能导致对母亲和儿童的重大干预。

Summary/Abstract: The risk for developing future psychiatric and addiction disorders starts early in life, with evidence emphasizing the critical contribution of the in utero environment. Maternal psychosocial stress has a significant impact on the prenatal environment and contributes to negative health and neurobehavioral outcomes in offspring. Our research (Stress in Pregnancy, SIP study), along with that of others, has shown that in utero exposure to maternal psychosocial stress is a major predictor of the risk for fear-related and impulse control-related problems during early childhood. We are now well positioned to conduct a long-term follow-up of our unique racially and financially diverse SIP study population to identify biomarkers of children’s behavior and physiological reactivity relevant for future subsequent behavioral disorders and addictive risk. Despite its importance, few studies have investigated placental molecular signatures to bio-behavioral assessments from early life through the pre/pubertal phase. Exploiting the SIP study's bio-repositories and deep-phenotyped child behaviors, our preliminary results show that epigenetic changes of the hypothalamic-pituitary-adrenal (HPA) axis and immune systems are associated with fear, anxiety, and emotion dysregulation among children exposed to in utero maternal stress. The SIP study cohort has many strengths: its consistent long-term follow-up, from in utero, its diversity (financially and racially), its extensive repository of stored biospecimens (placenta, toenail, hair samples), and its quasi-experimental design. The cohort is now entering pre/puberty (ages 9-13), a time for rapid social and biological transition and a peak time for the emergence of maladaptive, risk-taking behaviors with the brain still developing cognitive functions. Using this unparalleled opportunity, we will follow the cohort to 1) examine the role of exposure to SS in utero along with the effect of postnatal stress (normative stress, parenting) on neurodevelopmental functioning, as measured by multiple behavioral, physiological, and neuropsychological assessments; 2) determine the relationship between the prenatal epigenome signature in the placenta (along with an a priori focus on the HPA-axis and immune network genes) on the subsequent risk for negative behavioral characteristics (i.e., excessive anxiety and disruptive behaviors) and impaired executive functioning, known to elevate the risk for early initiation of substance use. Following our prior work, we will also examine sex-specific manifestations of the behavioral phenotypes (more internalizing problems in girls and externalizing in boys). We will further explore the moderating role of socioeconomic status when intersecting with prenatal SS-stress and postnatal stress on individual differences in cognitive neuro-behaviors, which make pre/pubescent children more vulnerable for a subsequent onset of behavioral and addictive disorders. We will build on our unique repository of stored biospecimens and profile chromatin accessibility across the epigenome and RNA expression network in the placenta. Given the steeply increasing incidence of adverse stressors, especially natural disasters (e.g., hurricanes, wildfires and pandemics), investigation of the short- and long-term impact of SS-stress on neurodevelopment from in utero through pre/puberty, will help us to identify problems and potentially lead to significant interventions for mother and child.