Epigenetic signatures linking maternal adversity and infant neurobiology

摘要 儿童时期的逆境占人口的50%-75%是酗酒、吸毒、 抑郁和自杀。成年人童年时期遭受虐待的经历往往会导致代际 虐待或疏忽的父母行为的传递，孩子压力反应中的失调 在父母和孩子中，精神疾病的风险都很高。新出现的研究表明 全基因组甲基化和加速的表观遗传老化也与儿童既往经历有关 虐待。然而，还没有研究评估表观遗传衰老和甲基化的程度 人类母亲及其婴儿的模式参与传递早期逆境的影响 母子相传。该提案寻求资金支持对银行母婴进行表观遗传分析。 唾液样本与派博士克里·雷斯勒的表观遗传学实验室合作，以允许分析 与母婴应激调节、母婴相互作用质量、 和婴儿边缘脑的发育。我们将利用我们团队拥有的数据来解决这一问题 根据R01HD079484收集(多PI的Teicher博士，McLean医院；Lyons-Ruth博士，剑桥医院； 波士顿儿童医院的博斯奎特·恩洛和格兰特博士)，来自150名母婴二人组，加权 在4个月和15个月婴儿年龄时评估母亲的儿童期虐待。这项建议的第一个目的是 将评估母亲童年虐待是否与表观遗传衰老加速有关，以及 母亲和婴儿全基因组DNA甲基化的差异，第二个目标将评估 母婴的表观遗传状态与非典型的母婴皮质醇反应有关。第三个目标 将评估照料质量是否与母亲的表观遗传状态和婴儿的表观遗传状态有关。这个 最终目的是评估婴儿的表观遗传状态是否与婴儿边缘脑的改变有关 区域，特别是杏仁核和海马体。这项倡议将由多名调查人员领导， 以下方面的专门知识：(1)表观遗传编程；(2)儿童期虐待的神经生物学效应(3)产妇 护理质量；(4)新生儿神经影像。儿时的逆境和父母教养方式的中断是根源 一系列医疗和精神疾病的可预防原因，导致巨大的公共卫生成本。 有必要详细了解潜在的机制、关键时间点和中介因素 确定婴儿风险的早期生物标志物，并设计有针对性的干预措施，以先发制人 早期逆境的后果。我们预计，目前的提案将确定具体的风险生物标记物 在婴儿期是可衡量的，目前是缺乏的。这些生物标志物将有助于早期的发展。 预防与压力相关的健康、心理健康、认知和成瘾的沉重负担的干预措施 这些婴儿面临的问题风险更大。

Abstract Childhood adversity accounts for 50-75% of the population attributable risk for alcoholism, drug abuse, depression, and suicide. Adults’ experiences of maltreatment in childhood often lead to the intergenerational transmission of abusive or neglectful parenting behaviors, dysregulation in their children’s stress response systems, and heightened risk for psychopathology in both parent and child. Emerging research suggests that genome-wide methylation and accelerated epigenetic aging are also associated with prior experiences of child maltreatment. However, no studies have assessed the extent to which epigenetic aging and methylation patterns in human mothers and their infants are involved in conveying the impact of early adversity from mother to child. This proposal seeks funding to support epigenetic assaying of banked maternal and infant saliva samples in collaboration with the epigenetics lab of PI Dr. Kerry Ressler to allow the analysis of the resultant epigenetic data in relation to maternal and infant stress regulation, maternal-infant interaction quality, and development of the infant limbic brain. We will address this agenda by leveraging data our team has collected under R01HD079484 (Multi PI’s Dr. Teicher, McLean Hospital; Dr. Lyons-Ruth, Cambridge Hospital; Drs. Bosquet Enlow and Grant, Boston Children’s Hospital) from 150 mother-infant dyads, weighted for maternal childhood maltreatment and assessed at 4 and 15 months infant age. The first aim of this proposal will evaluate whether maternal childhood maltreatment is linked to acceleration of epigenetic aging and differential genome-wide DNA methylation in both mothers and infants, The second aim will assess whether maternal and infant epigenetic status are linked to atypical maternal and infant cortisol reactivity. The third aim will assess whether caregiving quality is related to maternal epigenetic status and infant epigenetic status. The final aim will assess whether infant epigenetic status is associated with alterations in infant limbic brain regions, particularly the amygdala and hippocampus. This initiative will be led by multiple investigators with specific expertise in: (1) epigenetic programming; (2) neurobiological effects of childhood abuse (3) maternal caregiving quality; and (4) neonatal neuroimaging. Childhood adversity and disrupted parenting are the root preventable causes for a host of medical and psychiatric disorders that result in enormous public health costs. A detailed understanding of underlying mechanisms, critical time points, and mediating factors is necessary to identify early biomarkers for infant risk and to design targeted interventions to preempt the intergenerational consequences of early adversity. We expect that the current proposal will identify specific biomarkers for risk measurable in infancy, which are currently lacking. Such biomarkers will contribute to the development of early interventions to prevent the substantial burden of stress-related health, mental health, cognitive, and addictive problems these infants are at increased risk to experience.