Fungaro Rissatti Luciana, Wilson David, Palace-Berl Fanny, de Mello Ponteciano Bárbara, Sardela de Miranda Flávia, Alece Arantes Moreno Ivana, Dos Santos Vieira Tamires, Pereira Sorroche Bruna, Rebolho Batista Arantes Lidia Maria, Madeira Alvares da Silva Adriana, D'Almeida Vânia, Demarzo Marcelo, Rodrigues de Oliveira Daniela
Department of Pathology, Graduate Program in Pathology, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Department of Preventive Medicine, Graduate Program in Collective Health, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Brain Behav Immun Health. 2024 Oct 31;42:100900. doi: 10.1016/j.bbih.2024.100900. eCollection 2024 Dec.
The brain-derived neurotrophic factor (BDNF) gene plays an important role in modulating the stress-response axis and inflammation, which can be regulated by epigenetic mechanisms. BNDF methylation has been associated with stress-related psychiatric disorders such as depression, anxiety and post-traumatic stress. Previous studies have reported that stressful events are involved with long-lasting alterations in DNA methylation (DNAm) of the BNDF exon IV promoter, suggesting that glucocorticoids and inflammatory cytokines can regulate this process. We previously found that perceived psychological stress is modulated by inflammatory cytokines, such as interleukin (IL)-6, IL-8 and IL-10, and IL-12p70, suggesting their role in mediating the stress response. However, the epigenetic mechanism mediating this response has yet to be fully understood. In this study, we propose that high perceived stress and high serum levels of inflammatory cytokines may correlate with specific methylation sites within the BNDF exon IV promoter. To address these questions, we conducted a cross-sectional study of 82 adult women teachers working in basic education in Brazil. The perceived stress scale was used to assess stress and blood samples were collected for the measurement of inflammatory markers and BNDF methylation through flow cytometry assay and DNA pyrosequencing, respectively. We detected differentially methylated CpG sites in the gene, where 5 CpG sites were directly correlated with high stress levels. However, 4 CpG sites showed inverse effects, indicating that changes in methylation levels in those sites could lead to a protective effect on perceived stress. About inflammatory markers, IL-6 and IL-8 were associated with high perceived stress. However, only IL-8 and IL-10 showed simultaneous modulation of perceived stress, while IL-10 and IL12p70 correlated with DNAm. We found that higher levels in IL-10 and IL-12p70 serum decrease methylation in CpG11. A direct relationship was also found to IL-12p70, where higher levels in serum increase methylation in CpG5 and 13, respectively. Taken as a whole, our findings reinforce the hypothesis regarding stress-sensitive regions within the BDNF gene, mainly for CpG5, 11, and 13. In addition to these results, CpG7 and 9 may be regarded as stress-protective regions. Our data suggest that BDNF DNAm in the blood may represent a novel biomarker for early detection of adverse effects of chronic exposure to stress in healthy individuals.
脑源性神经营养因子（BDNF）基因在调节应激反应轴和炎症方面发挥着重要作用，其可通过表观遗传机制进行调控。BDNF甲基化与抑郁、焦虑和创伤后应激等应激相关精神障碍有关。先前的研究报道，应激事件与BDNF外显子IV启动子的DNA甲基化（DNAm）的长期改变有关，这表明糖皮质激素和炎性细胞因子可调节这一过程。我们先前发现，感知到的心理应激受到炎性细胞因子如白细胞介素（IL）-6、IL-8、IL-10和IL-12p70的调节，这表明它们在介导应激反应中发挥作用。然而，介导这种反应的表观遗传机制尚未完全明确。在本研究中，我们提出，高感知应激和高血清水平的炎性细胞因子可能与BDNF外显子IV启动子内的特定甲基化位点相关。为解决这些问题，我们对巴西82名从事基础教育的成年女教师进行了一项横断面研究。使用感知应激量表评估应激，并分别通过流式细胞术检测和DNA焦磷酸测序收集血样以测量炎性标志物和BDNF甲基化。我们在该基因中检测到差异甲基化的CpG位点，其中5个CpG位点与高应激水平直接相关。然而，4个CpG位点显示出相反的作用，表明这些位点甲基化水平的变化可能对感知应激产生保护作用。关于炎性标志物，IL-6和IL-8与高感知应激相关。然而，只有IL-8和IL-10同时调节感知应激，而IL-10和IL12p70与DNAm相关。我们发现，血清中IL-10和IL-12p70水平升高会降低CpG11的甲基化。还发现IL-12p70存在直接关系，血清中较高水平分别增加CpG5和13的甲基化。总体而言，我们的研究结果强化了关于BDNF基因内应激敏感区域（主要是CpG5、11和13）的假设。除了这些结果，CpG7和9可被视为应激保护区域。我们的数据表明，血液中的BDNF DNAm可能代表一种用于早期检测健康个体慢性应激不良影响 的新型生物标志物。
