Environment and Gene Effects on Brain and Behavior

描述（由申请人提供）：铅（Pb）对发育中的大脑的影响已经研究了几十年，但我们对这种环境毒物如何影响大脑发育和功能的理解仍然存在差距。遗传背景对铅对神经系统发育和功能的影响的改变，以及铅与基因组相互作用产生长期行为和其他影响的方式大多是未知的。这些研究问题是与此竞争性修订申请相关的家长补助金的基础。然而，为了更充分地了解铅-基因组相互作用，还需要研究对表观基因组的影响。特别是，这一竞争性修订应用将主要关注全基因组铅诱导的甲基化改变，特别是甲基化状态和MeCP2（一种参与多种基因转录调节的DNA结合蛋白）表达的变化，并与神经元成熟和可塑性以及各种认知和行为障碍（包括Rett综合征、自闭症、智力迟钝、多动症和学习障碍）密切相关。由于最近的研究表明，环境毒物可以通过影响表观遗传机制来影响基因组的完整性，因此需要研究不同水平和类型的铅暴露对基因组完整性的影响程度。因此，本申请中提出的研究有以下具体目的：评估不同类型和水平的发育性铅暴露对DNA甲基化和特别是MeCP2表达/甲基化的表观遗传影响的程度，以及这些影响与性别和行为结果的关联程度。这些研究将研究雄性和雌性动物中不同类型和水平的铅暴露对全基因组DNA甲基化的影响程度，以及海马中MeCP2启动子甲基化和MeCP2蛋白表达异常的程度，海马是已知在功能上受发育性铅暴露影响的大脑区域。然后，我们将把这些发现与行为结果联系起来。我们的假设是，铅暴露会导致神经发育障碍，从根本上说，是一种可塑性障碍，与表观遗传基因调控的改变（即DNA甲基化的改变）有关，这些影响可能因性别而异。

DESCRIPTION (provided by applicant): The effects of lead (Pb) on the developing brain have been studied for decades but there are still gaps in our understanding of how this environmental toxicant influences brain development and function. The modification of Pb's influences on nervous system development and function by genetic background and the manner in which Pb interacts with the genome to produce long-lasting behavioral and other effects are mostly unknown. These research questions are the basis of the parent grant associated with this competitive revision application. However, to more fully understand Pb-genome interactions, effects on the epigenome also need to be studied. In particular, this competitive revision application will focus in general on genome-wide Pb-induced alterations in methylation and in particular, on changes in methylation state and expression of MeCP2 (a DNA binding protein involved in transcriptional regulation of a multitude of genes) and critically involved in neuronal maturation and plasticity as well as a variety of cognitive and behavioral disorders including Rett syndrome, autism, mental retardation, ADHD, and learning disabilities. Since recent studies suggest that environmental toxicants can affect the integrity of the genome through effects on epigenetic mechanisms, the extent to which this occurs with different levels and types of Pb exposure need to be studied. Thus, the research proposed in this application has the following specific aim: Specific Aim. Assess the extent to which different types and levels of developmental lead exposure result in epigenetic influences on DNA methylation and MeCP2 expression/methylation in particular and the extent to which these effects correlate with gender and behavioral outcome. These studies will examine the extent to which different types and levels of lead exposure in male and female animals influence DNA methylation on a genome-wide basis and the extent to which there is aberrant MeCP2 promoter methylation and MeCP2 protein expression in the hippocampus, a brain regions known to be functionally affected by developmental lead exposure. We will then correlate these findings with behavioral outcomes. Our hypothesis is that lead exposure leads to a neurodevelopmental disorder, fundamentally, a disorder of plasticity, related to altered epigenetic gene regulation (i.e., alterations in DNA methylation) and that these effects may vary with gender. PUBLIC HEALTH RELEVANCE: The proposed research will provide new data on the effects of developmental lead exposure on epigenetic modifications (i.e., modifications to genes that do not involve changes in the DNA sequence). Recent reports suggest that environmental toxicants may affect the integrity of the genome and can do so through epigenetic mechanisms. Understanding effects of developmental lead exposure on the epigenome may help to tie together basic, clinical and epidemiological data showing effects on a multitude of diverse physiological processes and outcomes including impairments in neuronal structure and functioning and impairments in cognitive, social, language and motor skills that persist into adulthood.