Suzhou Medical College, Soochow University, Suzhou, China.
Suzhou Medical College, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
J Hazard Mater. 2023 Sep 5;457:131749. doi: 10.1016/j.jhazmat.2023.131749. Epub 2023 Jun 2.
A growing body of evidence indicates that ambient fine particle matter (PM) exposure inhibits heart development, but the underlying mechanisms remain elusive. We hypothesized that mA RNA methylation plays an important role in the cardiac developmental toxicity of PM. In this study, we demonstrated that extractable organic matter (EOM) from PM2.5 significantly decreased global mA RNA methylation levels in the heart of zebrafish larvae, which were restored by the methyl donor, betaine. Betaine also attenuated EOM-induced ROS overgeneration, mitochondrial damage, apoptosis and heart defects. Furthermore, we found that the aryl hydrocarbon receptor (AHR), which was activated by EOM directly repressed the transcription of methyltransferases mettl14 and mettl3. EOM also induced genome-wide mA RNA methylation changes, which led us to focus more on the aberrant mA methylation changes that were subsequently alleviated by the AHR inhibitor, CH223191. In addition, we found that the expression levels of traf4a and bbc3, two apoptosis related genes, were upregulated by EOM but restored to control levels by the forced expression of mettl14. Moreover, knockdown of either traf4a or bbc3 attenuated EOM-induced ROS overproduction and apoptosis. In conclusion, our results indicate that PM induces mA RNA methylation changes via AHR-mediated mettl14 downregulation, which upregulates traf4a and bbc3, leading to apoptosis and cardiac malformations.
越来越多的证据表明，环境细颗粒物（PM）暴露会抑制心脏发育，但潜在机制仍不清楚。我们假设 mA RNA 甲基化在 PM 的心脏发育毒性中发挥重要作用。在这项研究中，我们证明了 PM2.5 中的可提取有机物（EOM）显著降低了斑马鱼幼虫心脏中的全局 mA RNA 甲基化水平，而供甲基的甜菜碱可以恢复这种水平。甜菜碱还减轻了 EOM 诱导的 ROS 过度生成、线粒体损伤、细胞凋亡和心脏缺陷。此外，我们发现 EOM 直接激活的芳香烃受体（AHR）会抑制甲基转移酶 mettl14 和 mettl3 的转录。EOM 还诱导了全基因组 mA RNA 甲基化变化，这促使我们更加关注随后被 AHR 抑制剂 CH223191 减轻的异常 mA 甲基化变化。此外，我们发现 traf4a 和 bbc3 的表达水平上调，这两个与细胞凋亡相关的基因在 EOM 作用下上调，但在 mettl14 的强制表达下恢复到对照水平。此外，traf4a 或 bbc3 的敲低均减轻了 EOM 诱导的 ROS 过度生成和细胞凋亡。总之，我们的结果表明，PM 通过 AHR 介导的 mettl14 下调诱导 mA RNA 甲基化变化，从而上调 traf4a 和 bbc3，导致细胞凋亡和心脏畸形。
