Epigenetic Biomarkers of Early Psychotropic Medication Exposure

描述(申请人提供)：本提案回应了广泛的挑战领域--翻译科学(15)，并回应了具体的挑战主题--15-MH-101：“精神药物对动物模型中神经发育和行为的影响”。在大脑发育的青春期前和青春期后，使用抗精神病药物、抗抑郁药物和抗癫痫药物引起了人们对精神药物暴露的功能影响的担忧。宫内环境构成了最早的发育环境，从而提供了一种创新的途径，在正式诊断的精神病理学开始之前，在后代可能的个体脆弱性的背景下，通过这种途径来审查早期药物暴露的影响。医学遗传学的进展强调了环境和遗传因素在建立发育轨迹方面的贡献，以及最近表观遗传学改变在预测神经发育结果方面的潜在重要性。利用新的表观遗传学方法和成熟的实验室技术，在一组经过实验室确认并量化的胎儿暴露的儿童中，我们将检验我们的假设，即“患有精神疾病的女性的后代表现出独特的表观遗传学特征，表明早期接触精神药物可能会对儿童功能发育产生长期负面影响。”具体地说，该项目的目标是：(1)对以前收集的脐带血样本(N=300)进行全基因组甲基化模式评估，以确定在母亲服用a)抗精神病药物、b)抗癫痫药物和c)抗抑郁药物的儿童中，哪些基因发生了差异甲基化；d)与d)母亲没有服用精神药物的对照组相比；以及(2)在每个药物暴露组中挑选25名具有最明显表观遗传学特征(总N=100)的子女，在实验室范式中进行测试，以评估目前荷尔蒙、社交、情感和神经认知功能的水平。从这项为期两年的提案中获得的数据将为与产前接触精神药物相关的表观遗传和儿童功能结果提供新的见解。

DESCRIPTION (provided by applicant): This proposal responds to the broad challenge area - Translational Science (15) and responds to the specific challenge topic - 15-MH-101: "Effect of psychotropic medications on neurodevelopment and behavior in animal models". The use of antipsychotics, antidepressants, and anti-epileptics in both pre-pubertal and post-pubertal windows of brain development raise concerns about the functional effects of psychotropic exposure. The intrauterine environment constitutes the earliest developmental milieu, thereby affording an innovative avenue by which to examine the impact of early drug exposure against a backdrop of potential individual vulnerability in offspring, prior to the onset of formally diagnosed psychopathology. Advances in medical genetics have underscored the contribution of both environmental and genetic factors in establishing developmental trajectories and, more recently, the potential importance of epigenetic alterations in predicting neurodevelopmental outcomes. Utilizing novel epigenetic methodology and established laboratory techniques in a well characterized cohort of children with laboratory confirmed and quantified fetal exposure, we will test our hypothesis that "the offspring of women with mental illness demonstrate unique epigenetic signatures indicative of the early exposure to psychotropic medications that may produce long term negative consequences for childhood functional development." Specifically, this project aims to: (1) perform a genome-wide evaluation of methylation patterns in previously collected umbilical cord blood samples (N=300) to identify genes that are differentially methylated in children whose mothers took a) antipsychotics, b) anti-epileptics, and c) antidepressant medications during their pregnancy compared to d) controls whose mothers did not take psychotropic medications; and (2) select 25 offspring within each medication exposure group with the most distinct epigenetic profiles (total N=100) to test in a laboratory paradigm evaluating current levels of hormonal, social, affective, and neurocognitive functioning. The data obtained from this 2-year proposal will provide novel insight into the epigenetic and child functioning outcomes associated with prenatal exposure to psychotropic medication.