Environmental exposures in early life: Epigenetics and neurodevelopment

描述(由申请人提供)：表观遗传效应被报道为产前环境暴露，如铅(铅)、杀虫剂、双酚A，以及压力和营养缺乏症，如叶酸或缺铁(ID)。大多数研究都考虑了单次曝光。然而，暴露在环境毒物、营养缺乏症或有害的饮食添加剂和压力源的混合物中是很常见的。这项初步研究将探索实际产前暴露(杀虫剂、铅和ID的混合物)的表观遗传学变化和神经发育结果。最重要的假设是，接触混合物与后代关键神经发育基因/通路的DNA甲基化模式的变化有关，这些基因/通路与晚年较差的神经认知功能有关。这项初步研究建立在国立卫生研究院资助的关于出生前和出生后环境暴露和ID对神经发育影响的项目基础上，涉及来自北京和杭州附近农村地区的队列，中国(2000名足月婴儿)。对婴儿的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个月时收集父母对环境暴露、铁状态、生长、行为、感觉系统以及运动和认知功能的测量。脐带血中检测到了200多种杀虫剂。脐带血样本已被冷冻保存，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甲基化的方法，具体目标如下：1)论证在中国的这些队列中使用Illumina Infinium HumanMethylation450珠芯片分析进行表观遗传学研究的可行性；2)确定与产前暴露混合物相关的全基因组DNA甲基化变化；以及3)确定可能介导暴露与神经发育标记物关联的表观遗传学变化。在从每个队列中选择96个脐带血样本进行DNA甲基化研究(总共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、创新的基于大脑的措施，以及北京的孕期环境暴露测量。我们选择了在动物模型中神经过程具有良好特征的特定结果：ABR(髓鞘形成)、带有ERP的识别记忆(海马体)和顺序学习(基底节)。根据中国的规定，表观遗传分析将在中国进行。生物信息学和生物统计学的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2000名婴儿池，以理清农药、铅和ID的表观遗传修饰；考虑暴露时机；定量验证DNA甲基化特征；并确定可通过营养干预改变的表观遗传-暴露-结果关系，以铁补充为例。

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.