Environmental exposures in early life: Epigenetics and neurodevelopment

描述（由申请人提供）：报告了产前环境暴露（如铅（Pb）、农药、双酚A）以及压力和营养缺乏（如叶酸或铁缺乏症（ID））的表观遗传效应。大多数研究考虑单次暴露。然而，暴露于环境毒物、营养缺乏或有害饮食添加剂和压力源的混合物是常见的。这项试点研究将探讨表观遗传变化和神经发育结果与现实生活中的产前暴露（农药，铅和ID的混合物）。总体假设是，暴露混合物与关键神经发育基因/通路的后代DNA甲基化模式的变化相关，这些基因/通路与以后生活中较差的神经认知功能有关。该试点研究建立在NIH资助的产前和产后环境暴露和ID对神经发育影响的项目基础上，涉及来自中国北京和杭州附近农村地区的队列（2000名足月婴儿）。婴儿研究共享相同的大脑行为概念框架。在出生/6周、9个月和18个月时收集环境暴露、铁状态、生长、行为、感觉系统以及运动和认知功能的父母研究指标。超过200种杀虫剂在脐带血中被检测。脐带血样本已冷冻保存用于基因分析。为了识别与暴露和神经发育相关的表观遗传修饰基因，我们提出了一种全基因组DNA甲基化方法，具体目的如下：1）证明使用Illumina Infinium HumanMethylation 450 BeadChip分析在中国这些队列中进行表观遗传学研究的可行性; 2）识别与产前暴露混合物相关的全基因组DNA甲基化变化;和3）鉴定可能介导暴露与神经发育标志物的关联的表观遗传变化。在从每个队列中选择96个脐带血样本进行DNA甲基化研究（总n = 192）时，我们优先考虑了母研究设计的独特特征：杭州高度复杂，创新的基于大脑的测量和北京怀孕期间的环境暴露测量。我们选择了神经过程在动物模型中得到充分表征的特定结果：ABR（髓鞘形成），ERP识别记忆（海马）和序列学习（基底神经节）。根据中国法规，表观遗传试验将在中国进行。生物信息学和生物统计学数据分析和解释将在密歇根大学进行。我们计划未来的研究，使用整个游泳池的2000名婴儿解开与农药，铅和ID的表观遗传修饰;考虑暴露时间;验证DNA甲基化谱定量;并确定表观遗传暴露结果的关系，可以修改营养干预，铁补充剂作为一个例子。

DESCRIPTION (provided by applicant): Epigenetic effects are reported for prenatal environmental exposures such as lead (Pb), pesticides, bisphenol A, and stress and nutrient deficiencies, such as folate or iron deficiency (ID). Most studies consider single exposures. However, exposure to mixtures of environmental toxicants, nutrient deficiencies or harmful dietary additives, and stressors is common. This pilot study will explore epigenetic changes and neurodevelopmental outcome with real-life prenatal exposures (mixtures of pesticides, Pb, and ID). The overarching hypothesis is that exposure mixtures are associated with changes in offspring DNA methylation patterns of key neurodevelopmental genes/pathways related to poorer neurocognitive function later in life. The pilot study builds on NIH-funded projects on neurodevelopmental impacts of pre- and postnatal environmental exposures and ID, involving cohorts from rural areas near Beijing and Hangzhou, China (2000 full-term infants). The infant studies share the same brain-behavior conceptual framework. Parent study measures of environmental exposures, iron status, growth, behavior, sensory systems, and motor and cognitive function were collected at birth/6 weeks, 9 and 18 months. Over 200 pesticides are assayed in cord blood. Cord blood samples have been saved frozen for genetic analyses. To identify epigenetically modified genes related to exposures and neurodevelopment, we propose a genome-wide DNA methylation approach, with the following Specific Aims: 1) To demonstrate feasibility of epigenetic studies using Illumina Infinium HumanMethylation450 BeadChip analysis in these cohorts in China; 2) To identify genome-wide DNA methylation changes associated with prenatal exposure mixtures; and 3) To identify epigenetic changes that may mediate the association of exposures with markers of neurodevelopment. In selecting 96 cord-blood samples from each cohort for DNA- methylation studies (total n = 192), we prioritized unique features of the parent study designs: highly sophisticated, innovative brain-based measures for Hangzhou and environmental exposure measurement during pregnancy for Beijing. We chose specific outcomes where neural processes are well-characterized in animal models: ABR (myelination), recognition memory with ERP (hippocampus), and sequence learning (basal ganglia). Per China regulations, epigenetic assays will be conducted in China. Bioinformatic and biostatistical data analysis and interpretation will occur at the University of Michigan. We plan future studies using the entire pool of 2000 infants to disentangle epigenetic modifications with pesticides, Pb, and ID; consider exposure timing; validate DNA methylation profiles quantitatively; and determine epigenetic-exposure- outcome relations that can be modified by nutritional intervention, with iron supplementation as an illustration.