Epigenetic Biomarkers of Early Psychotropic Medication Exposure

描述（由申请人提供）：本提案回应了广泛的挑战领域-转化科学（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”。抗精神病药、抗抑郁药和抗癫痫药在青春期前和青春期后脑发育窗口期的使用引起了对精神药物暴露的功能影响的关注。宫内环境构成了最早的发育环境，因此提供了一种创新的途径，通过这种途径，在正式诊断为精神病理的发病之前，研究早期药物暴露对后代潜在个体脆弱性的影响。医学遗传学的进步强调了环境和遗传因素在建立发育轨迹方面的贡献，最近，表观遗传改变在预测神经发育结果方面的潜在重要性。利用新颖的表观遗传学方法和已建立的实验室技术，我们将在一组经过实验室确认和量化的胎儿暴露的儿童中，验证我们的假设，即“患有精神疾病的妇女的后代表现出独特的表观遗传学特征，表明早期暴露于精神药物可能对儿童功能发育产生长期的负面影响。”具体而言，该项目旨在：（1)对先前收集的脐带血样本（N=300）的甲基化模式进行全基因组评估，以确定母亲在怀孕期间服用a）抗精神病药物，b)抗癫痫药物和c)抗抑郁药物的儿童与d)母亲未服用精神药物的对照组相比甲基化差异的基因；(2)在每个药物暴露组中选择25个具有最明显表观遗传特征的后代（总N=100），在实验室范式中进行测试，评估当前激素水平，社会，情感和神经认知功能。从这项为期2年的提案中获得的数据将为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.