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）以及应激和营养缺乏（如叶酸或铁缺乏 (ID)）的表观遗传效应。大多数研究考虑单次暴露。然而，接触环境毒物、营养缺乏或有害膳食添加剂以及压力源的混合物是很常见的。这项试点研究将探讨现实生活中产前暴露（农药、铅和 ID 的混合物）的表观遗传变化和神经发育结果。总体假设是，接触混合物与后代关键神经发育基因/通路 DNA 甲基化模式的变化有关，这些基因/通路与晚年神经认知功能较差有关。该试点研究以 NIH 资助的项目为基础，研究产前和产后环境暴露和智力障碍对神经发育的影响，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。家长研究测量了出生时/6周、9个月和18个月时的环境暴露、铁状况、生长、行为、感觉系统以及运动和认知功能。脐带血中检测了 200 多种农药。脐带血样本被冷冻保存以进行基因分析。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，具体目标如下： 1) 证明在中国这些人群中使用 Illumina Infinium HumanMmethylation450 BeadChip 分析进行表观遗传研究的可行性； 2) 确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（总共 n = 192）时，我们优先考虑了父研究设计的独特特征：杭州采用高度复杂、创新的基于大脑的测量方法，北京采用孕期环境暴露测量方法。我们选择了动物模型中神经过程得到充分表征的具体结果：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，表观遗传学检测将在中国进行。生物信息学和生物统计数据分析和解释将在密歇根大学进行。我们计划未来进行研究，使用 2000 名婴儿的全部样本来解开农药、铅和 ID 造成的表观遗传修饰；考虑曝光时间；定量验证 DNA 甲基化谱；并确定可通过营养干预来改变的表观遗传-暴露-结果关系，以补铁为例。

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.