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

• 批准号: 10405013
• 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
• 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/10405013
• 关键词: Academic achievement; Adult; Adverse event; Affect; Amines; Amygdaloid structure; Behavior; Behavior Therapy; Behavioral; Biological; Brain; Brain region; Caregivers; Caring; Child; Child Rearing; Cognitive; Communities; Complex; DNA Methylation; Data; 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 (Brain); 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; Poisoning; Population; Public Health; Research; Role; Social Behavior; Social Development; Social Environment; Socioeconomic Status; Testing; Time; Variant; Water; Weaning; Work; adverse outcome; base; behavioral outcome; blood lead; brain behavior; caregiving; classical conditioning; differential expression; 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; neurodevelopment; neurotoxicity; offspring; postnatal; relating to nervous system; resilience; response; restriction enzyme; sex; social; social factors; social interventions; transcriptome; transcriptome sequencing; transcriptomics; Academic achievement; Adult; Adverse event; Affect; Amines; Amygdaloid structure; Behavior; Behavior Therapy; Behavioral; Biological; Brain; Brain region; Caregivers; Caring; Child; Child Rearing; Cognitive; Communities; Complex; DNA Methylation; Data; 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 (Brain); 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; Poisoning; Population; Public Health; Research; Role; Social Behavior; Social Development; Social Environment; Socioeconomic Status; Testing; Time; Variant; Water; Weaning; Work; adverse outcome; base; behavioral outcome; blood lead; brain behavior; caregiving; classical conditioning; differential expression; 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; neurodevelopment; neurotoxicity; offspring; postnatal; relating to nervous system; resilience; response; restriction enzyme; sex; social; social factors; social interventions; transcriptome; transcriptome sequencing; transcriptomics

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，并随后的认知和事物 功能。有助于最佳神经发育的因素之一是产后的丰富性 环境和照料质量都被证明会影响大脑，行为和社会发展 后代的选项。但是，环境暴露有能力使神经和认知/行为脱轨 发育，终生负面后果。发育范围（PB），重要的 公共卫生问题，可能会影响所有人口，但是，社会经济地位低（SES）的成员 城市的暴露风险更高，维持最高的血液PB水平，并有不利的结果 可能更严重。低SE对认知和行为发展的影响是多因素 但是，家乡环境的父母护理和质量的差异似乎起着重要作用。这些如何 因素分别起作用并相互作用以调节大脑对PB的表观遗传和转录反应 尚未检查姿势和影响认知/行为结果。我们实验室的先前研究 新的初步数据表明，海马（HIPP）和额叶皮质（FC）和反式的DNA甲基化 HIPP中的描述性概况受到产后环境的质量和PB暴露的调节， 是关联学习，记忆和执行功能。但是，孕产妇质量的影响 在PB神经毒性的实验研究中，尚未将护理视为效应修饰剂，也没有 物物护理的综合影响和后断奶后的社会环境的质量是研究的。 初步数据首次显示孕产妇护理的质量是有毒的重要效果修饰符 PB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 天然和行为的定义是由发育PB暴露产生的，并且可以通过进一步的变化来做到这一点 甲基化和转录曲线的最初通过PB暴露而改变。拟议的研究将 通过以下特定目的进行调查：目标1：检查社会差异的程度 孕产妇护理的环境和质量独立或共同修改男性的认知/行为结果 和患有发育性PB暴露的女性； AIM 2：确定关键的基因级甲基化变化，HIPP， FC和AMYG（使用甲基化依赖性免疫沉淀测序（MEDIP-SEQ）和甲基化 - 敏感限制酶消化测序（MRE-SEQ））和转录/功能网络变化 （使用RNA-seq）受发展PB暴露影响以及更改的轮廓的程度 由孕产妇护理和/或环境丰富的质量调节。这些研究将提供新的 关于环境/行为因素如何相互作用以影响神经发育脆弱性的形成 PB暴露后的弹性，并提供与了解生物基础有关的信息 与改善PB暴露的结果翻译有关的社会/行为干预措施。