Environmental exposures in early life: Epigenetics and neurodevelopment

生命早期的环境暴露：表观遗传学和神经发育

• 批准号: 8765374
• 负责人: Dana Dolinoy
• 金额: $ 23.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2016-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8765374
• 关键词: Address; Adverse effects; Affect; Affective; Animal Model; Attention; Basal Ganglia; Base of the Brain; Behavior; Bioinformatics; Biological; Biological Assay; Biological Markers; Birth; Blood specimen; Brain; Brain region; Buffers; China; Chinese People; Chronic; Cognitive; Cohort Studies; Collection; Country; DNA; DNA Methylation; DNA analysis; Data; Data Analyses; Developmental Gene; Diet; Dietary Intervention; Emotional; Environmental Exposure; Epigenetic Process; Exposure to; Family; Folic Acid Deficiency; Freezing; Funding; Future; Gender; Gene-Modified; Genes; Genomic DNA; Genomics; Goals; Growth; Heavy Metals; Hippocampus (Brain); Human; Impairment; Individual; Infant; Institutes; Intervention; Iron; Lead; Left; Life; Measurement; Measures; Mediating; Mediation; Methylation; Michigan; Modification; Motor; Neurocognitive; Neurodevelopmental Problem; Neurotoxins; Neurotransmitters; Nutrient; Outcome; Parents; Pathway interactions; Pattern; Performance at work; Perinatal Exposure; Pesticides; Pilot Projects; Policy Maker; Prefrontal Cortex; Pregnancy; Process; Public Health; Quality Control; Regulation; Regulator Genes; Reporting; Research Design; Sampling; Schools; Scientist; Sensory; Specimen; Stress; Structure; Testing; Time; Toxic Environmental Substances; Umbilical Cord Blood; United States National Institutes of Health; Universities; Visit; X Chromosome; base; bisphenol A; bisulfite; brain behavior; cognitive function; cohort; data integrity; early life exposure; epidemiology study; genetic analysis; genome-wide; innovation; iron deficiency; iron supplement; iron supplementation; lead exposure; memory recognition; myelination; neurodevelopment; nutrition; offspring; parent project; postnatal; prenatal; prenatal environmental exposure; prenatal exposure; prevent; public health relevance; relating to nervous system; rural area; sensorimotor system; sequence learning; social; stressor

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.

描述（由申请人提供）：据报道，诸如铅（PB），农药，双酚A以及胁迫和营养缺乏（例如叶酸或铁缺乏症（ID））的产前环境暴露（例如铅（PB），农药，双酚A）的表观遗传效应。大多数研究都考虑单一暴露。但是，很常见于环境有毒物质，营养缺乏或有害饮食添加剂和压力源的混合物。这项试点研究将通过现实产前暴露（农药，PB和ID的混合物）探索表观遗传变化和神经发育结果。总体假设是，暴露混合物与关键神经发育基因/途径的后代DNA甲基化模式的变化有关，与较差的神经认知功能有关。试点研究基于NIH资助的有关产前和产后环境暴露和ID的神经发育影响的项目，其中涉及来自中国北京和杭州附近的农村地区（2000年的2000名成熟婴儿）。婴儿研究具有相同的脑行为概念框架。父母研究在出生时/6周，9和18个月时收集了环境暴露，铁状态，生长，行为，感觉系统以及运动和认知功能的测量。用脐带血测定了200多种农药。脐带血样品已被保存冷冻以进行遗传分析。为了鉴定与暴露和神经发育有关的表观遗传修饰的基因，我们提出了一种全基因组DNA甲基化方法，以下具体目的：1）在中国，使用Illumina Infinium humanymethylation使用Illumina Infinium Infinium humanymethylation 450 Beadchip分析在中国的中国; 2）确定与产前暴露混合物有关的全基因组DNA甲基化变化； 3）确定可能介导暴露与神经发育标记的暴露缔合的表观遗传变化。在从每个队列中为DNA-甲基化研究中选择96个脐带血样品（总n = 192）时，我们优先考虑了父母研究设计的独特特征：高度精致的，基于脑海的基于大脑的措施和beijing妊娠期间的环境暴露测量。我们选择了特定的结果，其中神经过程在动物模型中得到充分表征：ABR（髓鞘），ERP（海马）识别记忆和序列学习（基底神经节）。根据中国法规，将在中国进行表观遗传测定。密歇根大学将发生生物信息学和生物统计数据分析和解释。我们计划使用2000名婴儿的整个池的未来研究，以通过农药，PB和ID解散表观遗传的修饰；考虑曝光时间；定量验证DNA甲基化谱；并确定可以通过营养干预来修改的表观遗传曝光关系，并以铁的补充作为例证。