Early Life Environment Modifies Behavioral, Epigenetic, and Transcriptional Outcomes from Developmental Lead Exposure

早期生活环境改变铅暴露导致的行为、表观遗传和转录结果

基本信息

批准号：
10624469
负责人：
JAY S SCHNEIDER
金额：
$ 51.6万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-14 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624469
关键词：
Academic achievement Adult Adverse event Affect Amygdaloid structure Association Learning Behavior Behavior Therapy Behavioral Biological Brain Brain region Caregivers Caring Child Child Rearing Classification Cognitive Communities Complex DNA Methylation Data Deterioration Development Digestion Disabled Persons Environment Environmental Exposure Environmental Impact Environmental Risk Factor Epigenetic Process Exposure to Female Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Hippocampus Home environment Immunoprecipitation Individual Infant Intervention Lead Lead levels Learning Life Life Experience Long-Term Effects Mediating Memory Methylation Modification Mothers Neurodevelopmental Deficit Neurotoxins Outcome Paint Perinatal Play Poison Poisoning Population Public Health Research Role Social Development Social Environment Socioeconomic Status Testing Time Variant Water Weaning Work adverse outcome base behavioral outcome blood lead caregiving differential expression environmental Pb exposure environmental enrichment for laboratory animals environmental intervention epidemiologic data executive function experience experimental study exposure route frontal lobe high risk improved outcome lead exposure low socioeconomic status male member methylome neural neurodevelopment neurotoxicity offspring postnatal resilience response restriction enzyme sex social social factors social interventions transcriptome transcriptome sequencing transcriptomics translation factor

项目摘要

Various environmental/behavioral factors can influence brain development and subsequent cognitive and be- havioral functioning. Among factors contributing to optimal neurodevelopment are the richness of the postnatal environment and caregiving quality, both of which have been shown to affect brain, behavior, and social devel- opment of offspring. Environmental exposures however, have the ability to derail neural and cognitive/behav- ioral development, with lifelong negative consequences. Developmental exposure to lead (Pb), an important public health problem, can affect all populations, however, members of low socioeconomic status (SES) com- munities are at higher risk of exposure, sustain the highest blood Pb levels, and have adverse outcomes that are potentially more severe. The effects of low SES on cognitive and behavioral development are multifactorial but variations in parental care and quality of the home environment appear to play important roles. How these factors act individually and interact to modulate the brain’s epigenetic and transcriptional responses to Pb ex- posure and affect cognitive/behavioral outcomes has not been examined. Previous studies from our lab and new preliminary data show that DNA methylation in the hippocampus (HIPP) and frontal cortex (FC) and trans- criptional profiles in HIPP are modulated by the quality of the postnatal environment and by Pb exposure, as are associative learning and memory and executive functioning. However, the impact of quality of maternal care has not been examined as an effect modifier in experimental studies of Pb neurotoxicity nor have the combined influences of maternal care and the quality of the post-weaning social environment been studied. Preliminary data show for the first time that quality of maternal care is an important effect modifier of the toxic influences of Pb exposure. Data suggest that different early life experiences may modify the expression of cog- nitive and behavioral deficits produced by developmental Pb exposure and may do so through further altera- tions of methylation and transcriptional profiles initially modified by Pb exposure. The proposed studies will investigate this through the following specific aims: Aim 1: Examine the extent to which variations in social en- vironment and quality of maternal care independently or jointly modify cognitive/behavioral outcomes in males and females with developmental Pb exposure; Aim 2: Identify critical gene-level methylation changes in HIPP, FC, and AMYG (using Methylation Dependent ImmunoPrecipitation sequencing (MeDIP-seq) and Methylation- sensitive Restriction Enzyme digestion sequencing (MRE-seq)) and transcriptional/functional network changes (using RNA-seq) that are affected by developmental Pb exposure and the extent to which altered profiles can be modulated by quality of maternal care and/or environmental enrichment. These studies will provide new in- formation on how environmental/behavioral factors may interact to influence neurodevelopmental vulnerability and resiliency following Pb exposure and provide information relevant to understanding the biological bases of social/behavioral interventions that are translationally relevant for improving outcomes from Pb exposure.

各种环境/行为因素都会影响大脑发育以及随后的认知和行为神经发育的最佳影响因素之一是产后的丰富性。环境和护理质量，这两者都已被证明会影响大脑、行为和社会发展。然而，后代的环境暴露有能力使神经和认知/行为脱轨。铅 (Pb) 是一种重要的发育接触，会对儿童的发育产生终生的负面影响。公共卫生问题可能会影响所有人群，但是，低社会经济地位（SES）群体的成员社区面临更高的暴露风险，维持最高的血铅水平，并产生不良后果，低社会经济地位对认知和行为发展的影响可能更为严重。但父母照顾和家庭环境质量的差异似乎发挥着重要作用。这些因素单独作用并相互作用，调节大脑对 Pb 的表观遗传和转录反应姿势和影响认知/行为结果尚未经过我们实验室之前的研究。新的初步数据表明，海马体 (HIPP) 和额叶皮层 (FC) 的 DNA 甲基化和反式 HIPP 的特征受到产后环境质量和铅暴露的调节，如然而，影响的是联想学习记忆和执行功能。在铅神经毒性的实验研究中，护理尚未被检验为一种效果调节剂，也没有被检验为铅神经毒性的实验研究。研究了产妇护理和断奶后社会环境质量的综合影响。初步数据首次显示孕产妇护理质量是有毒物质的重要影响调节剂数据表明，不同的早期生活经历可能会改变认知的表达。发育性铅暴露所产生的本质和行为缺陷，并可能通过进一步的改变来实现拟议的研究将最初通过铅暴露改变甲基化和转录谱。通过以下具体目标对此进行调查：目标 1：检查社会环境变化的程度环境和孕产妇护理质量独立或共同改变男性的认知/行为结果目标 2：确定 HIPP 中关键的基因水平甲基化变化， FC 和 AMYG（使用甲基化依赖性免疫沉淀测序 (MeDIP-seq) 和甲基化- 敏感的限制性酶消化测序（MRE-seq））和转录/功能网络变化（使用 RNA-seq）受发育 Pb 暴露的影响以及轮廓改变的程度这些研究将通过孕产妇护理质量和/或环境丰富来调节。形成环境/行为因素如何相互作用影响神经发育脆弱性和铅暴露后的弹性，并提供与了解其生物学基础相关的信息与改善铅暴露结果相关的社会/行为干预措施。