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.

项目摘要 发育过程中的单一毒物暴露会在成年后产生负面结果，随后会产生 几代人，在预防和治疗疾病方面构成了重大障碍。另外，给定 在退化生物学和遗传过程中对毒物的敏感性，老年的暴露是一个 关键的敏感窗口。尽管它们的意义，但是介导两个过程的机制是 理解不佳。铅（PB）仍然是主要公众的十个世界卫生组织识别的毒物之一 健康关注，即使已经有数十年的努力来管理环境路线 接触。大量研究表明，铅暴露对基因的有效神经毒性作用 表达和表观基因组，导致结果，例如I.Q.受损，行为失调和 语音和学习缺陷。我们的长期目标是确定环境有毒物质如何干扰 关键窗户期间的神经行为，以便预防和治疗成人发作和治疗的循证策略 可以开发转世疾病。 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节 神经行为表型。中心假设是在环境中相关的PB暴露 关键的敏感窗户（早期发展和老年）导致基因组和表观遗传失调， 改变神经发生途径在暴露和随后的世代中的功能。理由 拟议的研究是，对PB诱导的结果的机制的调查将推进 预防，风险评估，诊断和治疗策略。在强大的初步数据的指导下， 假设将通过追求三个具体目的来检验：1）确定生命阶段特定的转录组 发育和老年暴露于环境相关的神经发生途径的变化 PB水平； 2）确定与表型和遗传终点相关的表观基因组的新出现变化； 3） 确定由多代和转传的转录组和表观遗传学变化 祖先的暴露。最终，这些结果将确定生物标志物的关键窗口，并告知 介导有毒终点的途径之间的相互作用。