Epigenetics of Lead Toxicity in Mouse Brain

描述（由申请人提供）：学习障碍、注意力缺陷、攻击性和破坏性行为是早期铅暴露的长期后果。其他不良反应包括皮质灰质体积损失和功能缺陷，并伴有大脑重组的证据。有一个关键需要了解铅诱导的神经毒性的机制。本研究的长期目标是确定铅暴露延迟行为效应背后的机制，并治疗或预防这些行为。R21提案中概述的研究目的是确定铅暴露与大脑中的表观遗传、DNA甲基化模式之间是否存在关联。这项研究的中心假设是，产前和出生后早期暴露于铅导致脑损伤，与损伤区域的个体表观基因组的永久性修饰相关，这些修饰导致DNA甲基化的改变和随后的全球基因表达谱的变化。该项目的基本原理是，了解铅暴露导致的表观遗传变化以及它们如何与大脑异常相关，将揭示铅毒性的机制，并提出可能的预防策略。将完成以下具体目标：1）确定小鼠受铅暴露影响最大的大脑区域，2）对受铅暴露影响的大脑区域的DNA甲基化和基因表达进行比较分析。这些目标验证了一个工作假设，即铅暴露会导致大脑异常，这些异常可以通过成像检测到，并且受影响的大脑区域会发生表观遗传学改变。为了实现这些目标，将对妊娠期和生命早期暴露于不同剂量铅的小鼠进行成像，并对脑体积、白色物质完整性和神经化学进行定量，并将其与血铅水平相关联。在那些显示铅暴露影响的区域，将确定与未暴露小鼠相应区域不同的整体DNA甲基化和基因表达模式。预期的贡献是更好地理解铅神经毒性延迟表现的基本机制。这一贡献将是重要的，因为它将提供直接的证据，证明铅暴露和大脑发育变化之间的因果关系，可以解释这种暴露的延迟行为影响。一旦获得这些信息，就有可能通过药理学、饮食和营养因素进行预防和干预。这项工作是创新的，因为它结合了先进的神经影像学研究铅中毒的动物模型与表观遗传学研究，以更好地了解铅暴露的长期后果。这项工作的预期成果是建立脑损伤和表观遗传变化之间的联系，这为确定这些表观遗传变化如何影响以后的生活奠定了基础。

DESCRIPTION (provided by applicant): Learning disorders, attention deficits, aggressive and disruptive behaviors are long-term consequences of early lead exposure. Other adverse effects include cortical gray matter volume loss and functional deficits with evidence of brain reorganization. There is a critical need to understand the mechanisms of lead-induced neurotoxicity. The long-term goal of this research is to identify the mechanisms behind the delayed behavioral effects of lead exposure and to treat or prevent those behaviors. The objective of the studies outlined in this R21 proposal is to determine whether an association exists between lead exposure and epigenetic, DNA methylation patterns in the brain. The central hypothesis for this study is that prenatal and early postnatal exposure to lead causes brain injuries that are associated with permanent modifications of the individual epigenome in the injured regions and that these modifications cause alterations of DNA methylation and subsequent changes in global gene expression profiles. The rationale for this project is that knowing what epigenetic changes result from lead exposure and how they are associated with brain abnormalities will shed light on the mechanisms of lead toxicity, as well as suggest possible preventative strategies. The following specific aims will be completed: 1) determine brain regions most affected by lead exposure in mice and 2) conduct comparative analyses of DNA methylation and gene expression in the areas of brain affected by lead exposure. These aims test the working hypothesis that lead exposure results in brain abnormalities that are detectable with imaging and that epigenetic alterations occur in the affected brain regions. To achieve these aims, mice exposed to varying doses of lead during gestation and early life will be imaged and brain volumes, white matter integrity, and neurochemistry will be quantified and correlated with blood lead levels. In those regions showing an effect of lead exposure, global DNA methylation and gene expression patterns that differ from the corresponding areas in unexposed mice will be identified. The expected contribution is a better understanding of the fundamental mechanism(s) of the delayed manifestations of lead neurotoxicity. This contribution will be significant because it will provide direct evidence of the causal link between lead exposure and developmental brain changes that could explain the delayed behavioral effects of such exposure. Once this information is available, prevention and intervention through pharmacologic, dietary and trophic factors will be possible. This work is innovative because it combines advanced neuroimaging studies of lead intoxication in an animal model with epigenetic studies to better understand the long-term consequences of lead exposure. The expected outcome of this work is the establishment of a link between brain injury and epigenetic changes, which lays the foundation for determining how these epigenetic changes influence behavior later in life.