Department of Psychiatry, School of Medicine, Maltepe University, Istanbul, Turkey.
Department of Molecular Medicine, Institute of Health Sciences, Dokuz Eylul University, Izmir, Turkey.
Transl Psychiatry. 2024 May 24;14(1):207. doi: 10.1038/s41398-024-02901-3.
Previous evidence suggests elevated levels of oxidatively-induced DNA damage, particularly 8-hydroxy-2'-deoxyguanosine (8-OH-dG), and abnormalities in the repair of 8-OH-dG by the base excision repair (BER) in bipolar disorder (BD). However, the genetic disposition of these abnormalities remains unknown. In this study, we aimed to investigate the levels of oxidatively-induced DNA damage and BER mechanisms in individuals with BD and their siblings, as compared to healthy controls (HCs). 46 individuals with BD, 41 siblings of individuals with BD, and 51 HCs were included in the study. Liquid chromatography-tandem mass spectrometry was employed to evaluate the levels of 8-OH-dG in urine, which were then normalized based on urine creatinine levels. The real-time-polymerase chain reaction was used to measure the expression levels of 8-oxoguanine DNA glycosylase 1 (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1), poly ADP-ribose polymerase 1 (PARP1), and DNA polymerase beta (POLβ). The levels of 8-OH-dG were found to be elevated in both individuals with BD and their siblings when compared to the HCs. The OGG1 and APE1 expressions were downregulated, while POLβ expressions were upregulated in both the patient and sibling groups compared to the HCs. Age, smoking status, and the number of depressive episodes had an impact on APE1 expression levels in the patient group while body mass index, smoking status, and past psychiatric history had an impact on 8-OH-dG levels in siblings. Both individuals with BD and unaffected siblings presented similar abnormalities regarding oxidatively-induced DNA damage and BER, suggesting a link between abnormalities in DNA damage/BER mechanisms and familial susceptibility to BD. Our findings suggest that targeting the oxidatively-induced DNA damage and BER pathway could offer promising therapeutic strategies for reducing the risk of age-related diseases and comorbidities in individuals with a genetic predisposition to BD.
先前的证据表明，双相障碍（BD）患者体内氧化诱导的 DNA 损伤水平升高，尤其是 8-羟基-2'-脱氧鸟苷（8-OH-dG），以及碱基切除修复（BER）修复 8-OH-dG 的异常。然而，这些异常的遗传倾向仍不清楚。在这项研究中，我们旨在研究 BD 患者及其兄弟姐妹与健康对照组（HCs）相比，氧化诱导的 DNA 损伤和 BER 机制的水平。共纳入 46 名 BD 患者、41 名 BD 患者的兄弟姐妹和 51 名 HCs。采用液相色谱-串联质谱法（LC-MS/MS）评估尿液中 8-OH-dG 的水平，并根据尿液肌酐水平进行归一化。实时聚合酶链反应（PCR）用于测量 8-氧鸟嘌呤 DNA 糖基化酶 1（OGG1）、脱嘌呤/脱嘧啶内切酶 1（APE1）、多聚 ADP-核糖聚合酶 1（PARP1）和 DNA 聚合酶β（POLβ）的表达水平。与 HCs 相比，BD 患者及其兄弟姐妹的 8-OH-dG 水平均升高。与 HCs 相比，患者和兄弟姐妹组的 OGG1 和 APE1 表达下调，而 POLβ 表达上调。年龄、吸烟状况和抑郁发作次数对患者组 APE1 表达水平有影响，而体重指数、吸烟状况和既往精神病史对兄弟姐妹组 8-OH-dG 水平有影响。BD 患者及其未受影响的兄弟姐妹均存在氧化诱导的 DNA 损伤和 BER 异常，提示 DNA 损伤/BER 机制异常与 BD 的家族易感性之间存在关联。我们的研究结果表明，针对氧化诱导的 DNA 损伤和 BER 途径可能为具有 BD 遗传易感性的个体提供有前景的治疗策略，以降低与年龄相关的疾病和共病的风险。
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