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。其他副作用包括皮质灰质体积减少和功能障碍，并有大脑重组的证据。迫切需要了解铅致神经毒性的机制。这项研究的长期目标是确定铅暴露延迟行为影响背后的机制，并治疗或预防这些行为。R21提案中概述的研究目标是确定铅暴露与大脑中表观遗传DNA甲基化模式之间是否存在关联。这项研究的中心假设是，出生前和出生后早期暴露于铅会导致脑损伤，这些损伤与受损区域单个表观基因组的永久性修改有关，这些修改会导致DNA甲基化的改变，并随后改变全球基因表达谱。该项目的基本原理是，了解铅暴露导致的表观遗传变化及其与大脑异常的关系，将有助于阐明铅毒性的机制，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。这些目的是测试工作假说，即铅暴露会导致脑部异常，可以通过成像检测到，表观遗传变化发生在受影响的大脑区域。为了实现这些目标，在怀孕和早期生活中暴露于不同剂量铅的小鼠将被成像，脑体积、白质完整性和神经化学将被量化并与血铅水平相关联。在那些显示铅暴露影响的区域，将识别出与未接触铅的小鼠相应区域不同的全局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(S)。这一贡献将是重大的，因为它将提供直接证据，证明铅暴露与大脑发育变化之间的因果联系，这可能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、饮食和营养因素进行预防和干预。这项工作具有创新性，因为它将动物模型中铅中毒的高级神经成像研究与表观遗传学研究相结合，以更好地了解铅暴露的长期后果。这项工作的预期结果是在脑损伤和表观遗传变化之间建立了联系，这为确定这些表观遗传变化如何影响以后的生活行为奠定了基础。

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.