Department of Psychiatry, The Psychiatric Institute, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, USA.
Alcohol Clin Exp Res. 2013 Mar;37(3):417-24. doi: 10.1111/j.1530-0277.2012.01947.x. Epub 2012 Sep 7.
Recent studies suggest that protracted and excessive alcohol use induces an epigenetic dysregulation in human and rodent brains. We recently reported that DNA methylation dynamics are altered in brains of psychotic (PS) patients, including schizophrenia and bipolar disorder patients. Because PS patients are often comorbid with chronic alcohol abuse, we examined whether the altered expression of multiple members of the DNA methylation/demethylation network observed in postmortem brains of PS patients was modified in PS patients with a history of chronic alcohol abuse.
DNA-methyltransferase-1 (DNMT1) mRNA-positive neurons were counted in situ in prefrontal cortex samples obtained from the Harvard Brain Tissue Resource Center, Belmont, MA. 10-11-translocation (TETs 1, 2, 3), apolipoprotein B editing complex enzyme (APOBEC-3C), growth and DNA-damage-inducible protein 45β (GADD45β), and methyl-binding domain protein-4 (MBD4) mRNAs were measured by quantitative real-time polymerase chain reaction in inferior parietal cortical lobule samples obtained from the Stanley Foundation Neuropathology Consortium, Bethesda, MD.
We observed an increase in DNMT1 mRNA-positive neurons in PS patients compared with non-PS subjects. In addition, there was a pronounced decrease in APOBEC-3C and a pronounced increase in GADD45β and TET1 mRNAs in PS patients with no history of alcohol abuse. In PS patients with a history of chronic alcohol abuse, the numbers of DNMT1-positive neurons were not increased significantly. Furthermore, the decrease in APOBEC-3C mRNA was less pronounced, while the increase in TET1 mRNA had a tendency to be potentiated in those PS patients that were chronic alcohol abusers. GADD45β and MBD4 mRNAs were not influenced by alcohol abuse. The effect of chronic alcohol abuse on DNA methylation/demethylation network enzymes cannot be attributed to confounding demographic variables or to the type and dose of medication used.
Based on these results, we hypothesize that PS patients may abuse alcohol as a potential attempt at self-medication to normalize altered DNA methylation/demethylation network pathways. However, before accepting this conclusion, we need to study alterations in the DNA methylation/demethylation pathways and the DNA methylation dynamics in a substantial number of alcoholic PS and non-PS patients. Additional investigation may also be necessary to determine whether the altered DNA methylation dynamics are direct or the consequence of an indirect interaction of alcohol with the neuropathogenetic mechanisms underlying psychosis.
最近的研究表明，长期和过量饮酒会导致人类和啮齿动物大脑中的表观遗传失调。我们最近报道称，精神分裂症（PS）患者的大脑中 DNA 甲基化动态发生改变，包括精神分裂症和双相情感障碍患者。由于 PS 患者常伴有慢性酒精滥用，我们研究了在 PS 患者死后大脑中观察到的多个 DNA 甲基化/去甲基化网络成员的表达改变是否在有慢性酒精滥用史的 PS 患者中发生了改变。
在马萨诸塞州贝尔蒙特的哈佛脑组织资源中心获得的前额叶皮层样本中，原位计数 DNA 甲基转移酶-1（DNMT1）mRNA 阳性神经元。在马里兰州贝塞斯达的斯坦利基金会神经病理学联合会获得的下顶叶皮质叶样本中，通过定量实时聚合酶链反应测量 10-11 转位（TETs1、2、3）、载脂蛋白 B 编辑复合物酶（APOBEC-3C）、生长和 DNA 损伤诱导蛋白 45β（GADD45β）和甲基结合域蛋白-4（MBD4）mRNA。
与非 PS 受试者相比，我们观察到 PS 患者的 DNMT1 mRNA 阳性神经元增加。此外，在无酒精滥用史的 PS 患者中，APOBEC-3C 明显减少，GADD45β 和 TET1 mRNA 明显增加。在有慢性酒精滥用史的 PS 患者中，DNMT1 阳性神经元的数量没有显著增加。此外，APOBEC-3C mRNA 的减少不那么明显，而 TET1 mRNA 的增加则有增强的趋势，在那些慢性酒精滥用者中。GADD45β 和 MBD4 mRNA 不受酒精滥用的影响。慢性酒精滥用对 DNA 甲基化/去甲基化网络酶的影响不能归因于混杂的人口统计学变量或所使用的药物类型和剂量。
基于这些结果，我们假设 PS 患者可能会滥用酒精作为一种潜在的自我治疗方法，以使改变的 DNA 甲基化/去甲基化网络途径正常化。然而，在接受这一结论之前，我们需要在大量酒精性 PS 和非 PS 患者中研究 DNA 甲基化/去甲基化途径的改变和 DNA 甲基化动态。还需要进一步的研究来确定改变的 DNA 甲基化动力学是直接的，还是酒精与精神分裂症潜在神经发病机制的间接相互作用的结果。
