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），杀虫剂，双酚A）以及压力和营养缺乏（如叶酸或铁缺乏（ID））的表观遗传效应。大多数研究考虑的是单次暴露。然而，暴露于环境有毒物质、营养缺乏或有害膳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）。最重要的假设是，暴露混合物与后代关键神经发育基因/途径的DNA甲基化模式的变化有关，这些基因/途径与以后生活中较差的神经认知功能有关。该试点研究建立在美国国立卫生研究院资助的关于产前和产后环境暴露与ID的神经发育影响的项目上，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测量。脐带血中检测了200多种农药。脐带血样本已被冷冻保存以供基因分析。为了鉴定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，其具体目标如下：1)证明在中国这些队列中使用Illumina Infinium HumanMethylation450 BeadChip分析进行表观遗传研究的可行性；2)鉴定与产前暴露混合物相关的全基因组DNA甲基化变化；3)确定可能介导暴露与神经发育标志物关联的表观遗传变化。在从每个队列中选择96份脐带血样本进行DNA甲基化研究（总n = 192）时，我们优先考虑了父母研究设计的独特特征：杭州的高度复杂，创新的基于大脑的测量和北京的怀孕期间环境暴露测量。我们选择了在动物模型中具有良好特征的神经过程的特定结果：ABR（髓鞘形成）、ERP（海马）的识别记忆和序列学习（基底神经节）。根据中国规定，表观遗传学检测将在中国进行。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。我们计划未来使用整个2000名婴儿池进行研究，以解开农药、铅和ID对表观遗传修饰的影响；考虑曝光时机；定量验证DNA甲基化谱；并确定表观遗传-暴露-结果关系，可以通过营养干预进行修改，以补充铁为例。

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.