CNS Glucocorticoid Epigenetic Changes of Pb Stress Effects

描述（由申请人提供）：发育期铅（Pb）暴露和产前应激（PS）都会影响社会经济地位较低的社区，并以大脑中皮质边缘（MESO）系统和下丘脑-垂体-肾上腺（HPA）轴为目标。铅和PS联合作用可增强啮齿类动物的行为毒性，这与潜在的相互关联的MESO和HPA轴变化有关。在铅+/-PS小鼠的初步数据表明，海马糖皮质激素受体（GR）基因NR 3C 1的低甲基化在两种性别，随之而来的铅+PS小鼠的表达增加。铅差异改变额叶皮质组蛋白乙酰化（AcH 3 K9）水平的性别。因此，MESO GR表观遗传学的变化可能是铅+/-PS诱导的中枢神经系统毒性的重要机制。行为经验是后来的行为和大脑功能的关键决定因素，行为经验可以修改表观遗传标记。在我们的研究中，积极与消极的行为经验不仅区分MESO神经递质水平，但也改变了铅，PS和铅+PS对神经递质水平的影响。因此，对于充分理解Pb+/-PS的后果至关重要的是确定行为体验的性质如何减轻/逆转与进一步增强Pb和PS相关的表观遗传标记以及相关的CNS和HPA毒性。所提出的研究测试了以下假设：1）发育Pb+/-PS诱导性别依赖性MESO GR表观遗传变化，包括响应Pb+PS的增强的改变; 2）不同的行为体验（即，与“恢复力”相对于进一步病理学相关的那些）将导致表观遗传标记本身的差异谱，这可能与它们减轻或增强Pb和/或PS相关毒性的能力的差异有关。这些研究将显着提高中枢神经系统的表观遗传行为关系的理解，提供关键信息的机制，铅+/-PS的影响，并提供了一个基础，建立行为干预措施，可以帮助减轻影响铅+/-PS的影响，两个普遍存在的发展风险因素。

DESCRIPTION (provided by applicant): Both developmental lead (Pb) exposure and prenatal stress (PS) impact low socioeconomic status communities and target the brain mesocorticolimbic (MESO) system and the hypothalamic-pituitary-adrenal (HPA) axis. Combined Pb and PS in rodents can produce enhanced behavioral toxicity that is related to underlying inter-correlated MESO and HPA axis changes. Preliminary data in Pb+/-PS mice demonstrates hypomethylation of the hippocampal glucocorticoid receptor (GR) gene NR3C1 in both sexes with consequent increased expression in Pb+PS mice only. Pb differentially alters frontal cortex histone acetylation (AcH3K9) levels by gender. Thus MESO GR epigenetic changes may be important mechanisms of Pb+/-PS-induced CNS toxicity. Behavioral experience is a critical determinant of later behavior and brain function, and epigenetic marks can be modified by behavioral experiences. In our studies, positive vs. negative behavioral experience not only differentiated MESO neurotransmitter levels, but also altered the effects of Pb, PS and Pb+PS on neurotransmitter levels. Thus critical to a full understanding of the consequences of Pb+/-PS is a determination of how the nature of behavioral experience might either mitigate/reverse vs. further enhance Pb and PS- associated epigenetic marks, and associated CNS and HPA toxicity. The proposed studies test the hypotheses that: 1) developmental Pb+/-PS induce sex-dependent MESO GR epigenetic changes, including enhanced alterations in response to Pb+PS; 2) different behavioral experiences (i.e., those associated with 'resilience' vs. further pathology) after birth will result in differential profile of epigenetic marks per se that can be related to differences in their ability to mitigate or enhance Pb and/or PS-associated toxicity. These studies will significantly enhance the understanding of CNS epigenetic-behavioral relationships, provide critical information on mechanisms of Pb+/-PS effects, and provide a foundation for establishing behavioral interventions that could assist in mitigating effects of Pb+/-PS effects, two ubiquitous developmental risk factors.