Cui Yan, Li Zhan, Liu Yingyi, Wei Wencai, Yang Simei, Liu Xin, Chen Lei, Yan Haiquan, Li Gaoming, Zhou Qingying, Zhang Qingbi, Bai Jun
Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, Sichuan, China.
Luzhou Ecological Environment Monitoring Center of Sichuan Province, Southwest Medical University, Luzhou, China.
J Appl Toxicol. 2025 Nov;45(11):2412-2420. doi: 10.1002/jat.4858. Epub 2025 Jul 15.
PM has been linked to a variety of lung diseases. The objective of this study was to investigate the mechanism of lung inflammation caused by acute exposure to PM from the perspective of DNA methylation. Sprague-Dawley male rats were exposed to different concentrations of PM by non-exposure intratracheal instillation every other day for 3 times. Chemically modified si-Foxa1, si-Tet1, and si-NC were administered via the intratracheal instillation, followed by exposure to a medium concentration of PM. Fourteen days following the final exposure, serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected for the appropriate tests. Acute exposure to PM resulted in infiltration of inflammatory cells and destruction of the alveolar structure. The levels of IL-4 and eotaxin-1 in serum and BALF were increased, while the levels of interferon-γ (IFN-γ) were decreased. In lung tissues, there was a decrease in the whole genome 5-mC and an increase in 5-hmC. The methylation level of the interleukin-4 (IL-4) DNA promoter CpG islands decreased, accompanied by an increase in the mRNA level. The protein expression of Forkhead box A1 (FOXA1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) was upregulated. Downregulation of FOXA1 and TET1 levels reversed those changes. PM induced the upregulation of FOXA1 and TET1 protein expression, which subsequently affected the DNA methylation levels of IL-4. This, in turn, promoted the release of IL-4 and led to pulmonary inflammation. This study provides insights into the potential DNA methylation regulatory mechanisms underlying lung inflammation induced by acute PM exposure.
颗粒物（PM）已与多种肺部疾病相关联。本研究的目的是从DNA甲基化的角度探讨急性暴露于PM引起肺部炎症的机制。将Sprague-Dawley雄性大鼠每隔一天通过非暴露气管内滴注暴露于不同浓度的PM中，共进行3次。通过气管内滴注给予化学修饰的小干扰RNA（si-Foxa1、si-Tet1和si-NC），随后暴露于中等浓度的PM中。在最后一次暴露后14天，收集血清、支气管肺泡灌洗液（BALF）和肺组织进行相应检测。急性暴露于PM导致炎症细胞浸润和肺泡结构破坏。血清和BALF中白细胞介素-4（IL-4）和嗜酸性粒细胞趋化因子-1的水平升高，而干扰素-γ（IFN-γ）的水平降低。在肺组织中，全基因组5-甲基胞嘧啶（5-mC）减少，5-羟甲基胞嘧啶（5-hmC）增加。白细胞介素-4（IL-4）DNA启动子CpG岛的甲基化水平降低，同时mRNA水平升高。叉头框A1（FOXA1）和十一-易位甲基胞嘧啶双加氧酶1（TET1）的蛋白表达上调。下调FOXA1和TET1水平可逆转这些变化。PM诱导FOXA1和TET1蛋白表达上调，随后影响IL-4的DNA甲基化水平。这反过来又促进了IL-4的释放并导致肺部炎症。本研究为急性PM暴露诱导肺部炎症潜在的DNA甲基化调控机制提供了见解。
