CNS Glucocorticoid Epigenetic Changes of Pb Stress Effects

描述(由申请人提供)：发育铅(铅)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系统(MESO)和下丘脑-垂体-肾上腺(HPA)轴为目标。在啮齿动物体内，铅和多磺酸联合作用可产生增强的行为毒性，这与潜在的相互关联的中枢轴和HPA轴的变化有关。在铅/-PS小鼠中的初步数据显示，海马糖皮质激素受体(GR)基因NR3C1在两性中都发生了低甲基化，结果只在铅-PS小鼠中表达增加。铅对额叶皮质组蛋白乙酰化(AcH3K9)水平的影响因性别而异。因此，中位GR的表观遗传学改变可能是铅/PS诱导的中枢神经系统毒性的重要机制。行为经验是后来行为和大脑功能的关键决定因素，表观遗传标记可以通过行为经验来修改。在我们的研究中，积极和消极的行为体验不仅改变了MESO神经递质水平，而且改变了铅、PS和PbPS对神经递质水平的影响。因此，对于充分理解铅/-PS的后果，关键是确定行为经验的性质如何缓解/逆转或进一步增强与铅和PS相关的表观遗传标记，以及相关的CNS和HPA毒性。建议的研究验证了以下假设：1)发育的铅/-PS诱导性别相关的中GR表观遗传学变化，包括对铅-PS的反应增强的变化；2)出生后不同的行为经历(即，与‘弹性’和进一步的病理相关的那些)将导致表观遗传标记本身的不同特征，这可能与它们缓解或增强铅和/或PS相关毒性的能力的差异有关。这些研究将显著提高对中枢神经系统表观遗传-行为关系的理解，为铅/PS效应的机制提供关键信息，并为建立有助于减轻铅/PS效应这两种普遍存在的发育危险因素的行为干预提供基础。

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.