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

项目摘要 在发育过程中接触一次有毒物质会对成年期和随后的发育产生负面影响。 这是预防和治疗疾病的一个主要障碍。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， 关键敏感窗口尽管它们的重要性，然而，介导这两个过程的机制是 不太了解。铅（Pb）是世界卫生组织确定的10种主要公众有毒物质之一 健康问题，尽管已经有几十年的努力，以管理环境的路线， exposure.大量的研究表明，铅暴露对基因表达有潜在的神经毒性作用。 表达和表观基因组，导致诸如智商受损，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 神经行为在关键窗口，使循证策略，以预防和治疗成人发病， 可以发展成跨代疾病。本次NIEHS R 01奖的总体目标（PA-20-185） 应用是确定基因组功能改变和环境影响的表观遗传调节， 神经行为表型中心假设是，环境相关的铅暴露期间， 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， 改变暴露和后代的神经发生途径功能。的理由 拟议的研究是，铅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。在强大的初步数据指导下， 将通过追求三个具体目标来测试假设：1）确定生命阶段特异性转录组学， 发育和老年暴露于环境相关物质后神经发生途径的变化 铅水平; 2）确定表观基因组中与表型和遗传终点相关的紧急变化; 3） 确定多代和跨代转录组和表观遗传变化诱导的 祖先暴露最终，这些结果将确定生物标志物的关键窗口， 介导毒性终点的途径之间的相互作用。

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.