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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/行为因素可以影响大脑发育和随后的认知，口腔功能。在促进最佳神经发育的因素中，环境和生活质量，这两者都已被证明会影响大脑，行为和社会发展。子孙的机会。然而，环境暴露有能力破坏神经和认知/神经系统，道德发展，并带来终身的负面影响。铅（Pb）的发育暴露是一个重要的公共卫生问题，可以影响所有人口，但是，低社会经济地位（SES）的成员，社区暴露的风险更高，维持最高的血铅水平，并有不良后果，可能会更严重低社会经济地位对认知和行为发展的影响是多因素的但父母的照顾和家庭环境质素的差异，似乎亦扮演重要角色。如何将这些这些因素单独作用并相互作用，以调节大脑对铅前体的表观遗传和转录反应。尚未检查影响认知/行为结果的因素。我们实验室以前的研究，新的初步数据显示，海马（HIPP）和额叶皮质（FC）的DNA甲基化和反式- HIPP中的criptional配置文件受到出生后环境质量和铅暴露的调制，是联想学习记忆和执行功能然而，产妇的质量影响在铅神经毒性的实验研究中，没有将护理作为效应修饰剂进行检查，研究了产妇护理和断奶后社会环境质量的综合影响。初步数据首次表明，孕产妇护理质量是有毒物质的重要影响因素，铅暴露的影响。数据表明，不同的早期生活经历可能会改变cog的表达，发育期铅暴露可能会导致发育期的行为缺陷，并可能通过进一步的改变而产生。的甲基化和转录谱最初修改铅暴露。拟议的研究将通过以下具体目标进行调查：目标1：检查社会环境变化的程度，产妇护理的质量和质量独立或共同改变男性的认知/行为结果和发育期铅暴露的女性;目的2：确定HIPP中关键基因水平的甲基化变化， FC和AMYG（使用甲基化依赖性免疫沉淀测序（MeDIP-seq）和甲基化- 灵敏的限制性内切酶消化测序（MRE-seq））和转录/功能网络变化（使用RNA-seq）受发育期铅暴露的影响，以及改变的轮廓可以在多大程度上改变通过孕产妇护理质量和/或环境丰富程度进行调节。这些研究将提供新的信息- 环境/行为因素如何相互作用以影响神经发育脆弱性和弹性后，铅暴露，并提供有关的信息，了解生物基础，社会/行为干预，是预防相关的改善铅暴露的结果。