Transcriptomic and epigenetic mechanisms of lead (Pb)-induced neurobehavioral disease in aged populations and subsequent generations

铅（Pb）诱导的老年人群及后代神经行为疾病的转录组和表观遗传机制

• 批准号: 10577926
• 负责人: Tracie R Baker
• 金额: $ 33.57万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-17 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577926
• 关键词: Adult; Aging; Air; Award; Behavior; Behavioral; Behavioral Assay; Biological Markers; Biological Process; Brain; Brain region; Characteristics; Child; Chromatin; Cognition; Data; Development; Disease; Disease Outcome; Dose; Dust; Elderly; Embryo; Embryonic Development; Environment; Environmental Exposure; Epigenetic Process; Exhibits; Exposure to; Gene Expression; Generations; Genes; Genetic; Genetic Processes; Genome; Genomics; Goals; HDAC4 gene; Health; Heritability; Histology; Household; Hyperactive behavior; Impaired cognition; Impairment; Investigation; Laboratories; Lead; Lead Poisoning; Lead levels; Learning; Life; Link; Longevity; Mediating; Memory; Methods; Methylation; Modification; Molecular; Motor Activity; Mutation; National Institute of Environmental Health Sciences; Nervous System; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Outcome; Paint; Pathway interactions; Phenotype; Predisposition; Prevention; Process; Public Health; Research; Risk Assessment; Route; Series; Soil; Speech; Testing; Time; Toxic Environmental Substances; Toxicant exposure; Toy; Transgenic Organisms; United States; World Health Organization; Zebrafish; aged; aging population; behavioral response; blood lead; diagnostic strategy; disorder risk; drinking water; epigenetic regulation; epigenome; epigenomics; evidence base; histone modification; human old age (65+); lead exposure; neurobehavior; neurobehavioral; neurodevelopment; neurogenesis; neurotoxic; prevent; response; sex; toxicant; transcriptome; transcriptomics; transmission process; treatment strategy; urban children

PROJECT SUMMARY A single toxicant exposure during development can produce negative outcomes in adulthood and subsequent generations, presenting a major hurdle in the prevention and treatment of disease. In addition, given the susceptibility to toxicants amid degenerative biological and genetic processes, exposure during old age is a critical sensitive window. Despite their significance, however, the mechanisms that mediate both processes are poorly understood. Lead (Pb) remains one of ten World Health Organization-identified toxicants of major public health concern, even though there have been decades-long efforts to manage the routes of environmental exposure. Numerous studies have demonstrated potent neurotoxic effects of lead exposure on gene expression and the epigenome, resulting in outcomes such as impaired I.Q., behavioral dysregulation, and speech and learning deficits. Our long-term goal is to determine how environmental toxicants interfere with neurobehavior during critical windows so that evidence-based strategies to prevent and treat adult-onset and transgenerational disease can be developed. The overall objective for this NIEHS R01 Award (PA-20-185) application is to determine genome function alterations and epigenetic regulation of environmentally-influenced neurobehavioral phenotypes. The central hypothesis is that environmentally relevant Pb exposure during critical sensitive windows (early development and old age) lead to genomic and epigenetic dysregulation that alters neurogenesis pathway function in the exposed and subsequent generations. The rationale for the proposed research is that investigation of the mechanisms underlying Pb-induced outcomes will advance prevention, risk-assessment, diagnostic, and treatment strategies. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine life stage-specific transcriptomic changes in neurogenesis pathways following developmental and geriatric exposure to environmentally relevant Pb levels; 2) Determine emergent changes in the epigenome related to phenotypic and genetic endpoints; 3) Determine multigenerational and transgenerational transcriptomic and epigenetic changes induced by ancestral exposure. Ultimately, these results will identify critical windows for biomarkers of effect, and inform the interplay among pathways mediating toxic endpoints.

项目总结 在发育过程中接触一种单一的毒物会在成年及以后产生负面后果。 在预防和治疗疾病方面，这是一个重大障碍。此外，鉴于 在退化的生物和遗传过程中，老年期间暴露于毒物是一种 关键敏感窗口。然而，尽管它们意义重大，但调解这两个过程的机制是 人们对此知之甚少。铅仍然是世界卫生组织确定的十种主要公众毒物之一 健康问题，尽管几十年来一直在努力管理环境污染的路线 曝光。大量研究表明，铅暴露对基因有潜在的神经毒性作用。 表达和表观基因组，导致智商受损，行为失调，以及 语言和学习缺陷。我们的长期目标是确定环境毒物如何干扰 危重期间的神经行为，从而以循证策略预防和治疗成人发病和 可能会发展成跨代疾病。NIEHS R01奖(PA-20-185)的总体目标 应用于确定基因组功能改变和环境影响的表观遗传调控 神经行为表型。中心假设是与环境相关的铅暴露在 关键敏感窗口(早期发育和老年)导致基因组和表观遗传失调， 改变暴露的后代和后续世代的神经发生途径功能。该计划的基本原理 拟议的研究是，对铅诱导结果的潜在机制的调查将会取得进展 预防、风险评估、诊断和治疗策略。在强劲的初步数据指引下，这 假设将通过追求三个具体目标来检验：1)确定特定于生命阶段的转录 发育和老年环境相关暴露后神经发生通路的变化 PB水平；2)确定表观基因组中与表型和遗传终点有关的紧急变化；3) 确定由以下因素引起的多代和跨代转录和表观遗传学变化 祖传接触。最终，这些结果将确定影响生物标记物的关键窗口，并告知 介导毒物终点的途径之间的相互作用。