OBJECTIVE Glucocorticoid receptor gene (NR3C1) promoter methylation influences cellular expression of the glucocorticoid receptor and is a proposed mechanism by which early life stress impacts neuroendocrine function. Mitochondria are sensitive and responsive to neuroendocrine stress signaling through the glucocorticoid receptor, and recent evidence with this sample and others shows that mitochondrial DNA copy number (mtDNAcn) is increased in adults with a history of early stress. No prior work has examined the role of NR3C1 methylation in the association between early life stress and mtDNAcn alterations. METHODS Adult participants (n = 290) completed diagnostic interviews and questionnaires characterizing early stress and lifetime psychiatric symptoms. Medical conditions, active substance abuse, and prescription medications other than oral contraceptives were exclusionary. Subjects with a history of lifetime bipolar, obsessive-compulsive, or psychotic disorders were excluded; individuals with other forms of major psychopathology were included. Whole blood mtDNAcn was measured using qPCR; NR3C1 methylation was measured via pyrosequencing. Multiple regression and bootstrapping procedures tested NR3C1 methylation as a mediator of effects of early stress on mtDNAcn. RESULTS The positive association between early adversity and mtDNAcn (p = .02) was mediated by negative associations of early adversity with NR3C1 methylation (p = .02) and NR3C1 methylation with mtDNAcn (p < .001). The indirect effect involving early adversity, NR3C1 methylation, and mtDNAcn was significant (95 % CI [.002, .030]). CONCLUSIONS NR3C1 methylation significantly mediates the association between early stress and mtDNAcn, suggesting that glucocorticoid receptor signaling may be a mechanistic pathway underlying mtDNAcn alterations of interest for future longitudinal work.

中文翻译：

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与早期生活压力相关的神经内分泌功能和线粒体生物发生的分子标记


目的 糖皮质激素受体基因 (NR3C1) 启动子甲基化影响糖皮质激素受体的细胞表达，并且是早期生活压力影响神经内分泌功能的一种拟议机制。线粒体对通过糖皮质激素受体发出的神经内分泌应激信号敏感且反应灵敏，该样本和其他样本的最新证据表明，有早期应激史的成年人的线粒体 DNA 拷贝数 (mtDNAcn) 增加。之前没有研究探讨 NR3C1 甲基化在早期生活压力和 mtDNAcn 改变之间的关联中的作用。方法 成年参与者 (n = 290) 完成了诊断访谈和问卷调查，描述了早期压力和终生精神症状。医疗状况、活性物质滥用和口服避孕药以外的处方药均被排除在外。有终生双相情感障碍、强迫症或精神病史的受试者被排除在外；患有其他形式的主要精神病理学的个体也被包括在内。使用 qPCR 测量全血 mtDNAcn；通过焦磷酸测序测量 NR3C1 甲基化。多重回归和引导程序测试了 NR3C1 甲基化作为早期应激对 mtDNAcn 影响的中介因素。结果 早期逆境与 mtDNAcn (p = .02) 之间的正相关是由早期逆境与 NR3C1 甲基化 (p = .02) 和 NR3C1 甲基化与 mtDNAcn (p < .001) 的负相关介导的。涉及早期逆境、NR3C1 甲基化和 mtDNAcn 的间接影响非常显着 (95 % CI [.002, .030])。 结论 NR3C1 甲基化显着介导早期应激与 mtDNAcn 之间的关联，表明糖皮质激素受体信号传导可能是未来纵向研究感兴趣的 mtDNAcn 改变的潜在机制途径。