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.

项目概要 发育过程中接触单一有毒物质可能会在成年期和随后的时期产生负面结果 代代相传，成为预防和治疗疾病的主要障碍。此外，鉴于 在退化的生物和遗传过程中对有毒物质的敏感性，老年时期的暴露是一个 关键敏感窗口。然而，尽管它们很重要，但介导这两个过程的机制是 不太了解。铅 (Pb) 仍然是世界卫生组织确定的对主要公众有害的十种有毒物质之一 健康问题，尽管几十年来一直在努力管理环境污染的途径 接触。大量研究表明铅暴露对基因具有潜在的神经毒性作用 表达和表观基因组，导致智商受损、行为失调和 言语和学习缺陷。我们的长期目标是确定环境毒物如何干扰 关键窗口期的神经行为，以便制定基于证据的策略来预防和治疗成人发病和 可能会产生跨代疾病。 NIEHS R01 奖 (PA-20-185) 的总体目标 应用是确定受环境影响的基因组功能改变和表观遗传调控 神经行为表型。中心假设是环境相关的铅暴露 关键的敏感窗口（早期发育和老年）导致基因组和表观遗传失调， 改变暴露者及其后代的神经发生途径功能。理由如下： 拟议的研究表明，对铅引起的结果的潜在机制的研究将取得进展 预防、风险评估、诊断和治疗策略。在强有力的初步数据的指导下， 假设将通过追求三个具体目标来检验：1）确定生命阶段特异性转录组 发育和老年暴露于相关环境后神经发生途径的变化 铅含量； 2) 确定与表型和遗传终点相关的表观基因组的紧急变化； 3） 确定由以下因素引起的多代和跨代转录组和表观遗传变化 祖传的曝光。最终，这些结果将确定效果生物标志物的关键窗口，并告知 介导毒性终点的途径之间的相互作用。