CNS Glucocorticoid Epigenetic Changes of Pb Stress Effects

描述（由申请人提供）：发育铅（Pb）暴露和产前应激（PS）都会影响低社会经济地位的社区，并以大脑中脑皮质边缘（MESO）系统和下丘脑-垂体-肾上腺（HPA）轴为目标。Pb和PS在啮齿类动物体内可产生增强的行为毒性，这与潜在的相互关联的MESO和HPA轴变化有关。Pb+/-PS小鼠的初步数据显示两性海马糖皮质激素受体（GR）基因NR3C1的低甲基化，因此仅在Pb+PS小鼠中表达增加。铅对不同性别额叶皮质组蛋白乙酰化（AcH3K9）水平的影响存在差异。因此，MESO - GR表观遗传改变可能是Pb+/- ps诱导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，表观遗传标记可以被行为经验修改。在我们的研究中，积极和消极的行为体验不仅分化了中观神经递质水平，而且改变了Pb、PS和Pb+PS对神经递质水平的影响。因此，充分了解Pb+/-PS后果的关键是确定行为体验的本质如何减轻/逆转或进一步增强Pb和PS相关的表观遗传标记，以及相关的中枢神经系统和HPA毒性。本研究验证了以下假设：1)发育Pb+/-PS诱导性别依赖性MESO GR表观遗传改变，包括Pb+PS增强的改变；2)出生后不同的行为经历（即与“恢复力”和进一步病理相关的行为经历）将导致表观遗传标记本身的不同特征，这可能与它们减轻或增强铅和/或ps相关毒性的能力差异有关。这些研究将显著增强对中枢神经系统表观遗传-行为关系的理解，为Pb+/-PS效应的机制提供重要信息，并为建立有助于减轻Pb+/-PS效应这两种普遍存在的发育危险因素的行为干预奠定基础。

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.