Suzhou Medical College of Soochow University, Suzhou, China.
Toxicology, Risk Assessment, and Research Division, Texas Commission on Environmental Quality, 12015 Park 35 Cir, Austin, TX, USA.
Environ Pollut. 2023 Apr 15;323:121306. doi: 10.1016/j.envpol.2023.121306. Epub 2023 Feb 17.
Growing evidence indicates that maternal fine particulate matter (PM2.5) exposure is linked with congenital heart diseases in the offspring. To explore the underlying molecular mechanisms, we tested the effects of a number of pharmaceutical inhibitors, and found that suppressing the PI3K/akt signaling pathway had a protective effect against cardiac defects in zebrafish larvae exposed to extractable organic matter (EOM) from PM2.5. Using genetic knockdown and a specific akt2 pharmacological inhibitor, CCT128930, we demonstrated that akt2 activation is essential to EOM-induced heart malformations. Next, we found that the EOM-induced akt2 overactivation enhances intracellular reactive oxygen species (ROS)/mitochondrial ROS production, decreases mitochondrial membrane potential levels, and elicits intrinsic apoptosis in the heart of zebrafish embryos. In addition, EOM-induced akt2 activation decreased active β-catenin levels and inhibited the expression of Wnt target genes axin2 and nkx2.5. We further demonstrated that mTORC1 phosphorylation mediates the adverse effects of akt2 on intrinsic apoptosis and canonical Wnt signaling in the heart of zebrafish larvae exposed to EOM. Moreover, EOM-induced akt2 activation is mediated via aryl hydrocarbon receptor (AHR)/ROS-induced PTEN inhibition. In conclusion, our results indicate that PM2.5 activates PI3K/akt2/mTORC1 signaling via AHR/ROS-induced PTEN suppression, which leads to mitochondrial-mediated intrinsic apoptosis and Wnt signaling suppression, resulting in cardiac defects in zebrafish larvae.
越来越多的证据表明，母体细颗粒物（PM2.5）暴露与后代先天性心脏病有关。为了探索潜在的分子机制，我们测试了一些药物抑制剂的作用，发现抑制 PI3K/akt 信号通路对暴露于 PM2.5 可萃取有机物（EOM）的斑马鱼幼虫的心脏缺陷具有保护作用。通过基因敲低和特定的 akt2 药理学抑制剂 CCT128930，我们证明了 akt2 的激活对于 EOM 诱导的心脏畸形是必不可少的。接下来，我们发现 EOM 诱导的 akt2 过度激活增强了细胞内活性氧（ROS）/线粒体 ROS 的产生，降低了线粒体膜电位水平，并在斑马鱼胚胎的心脏中引发了内在凋亡。此外，EOM 诱导的 akt2 激活降低了活性 β-连环蛋白水平，并抑制了 Wnt 靶基因 axin2 和 nkx2.5 的表达。我们进一步证明，mTORC1 磷酸化介导了 akt2 对 EOM 暴露的斑马鱼幼虫心脏内在凋亡和经典 Wnt 信号通路的不良影响。此外，EOM 诱导的 akt2 激活是通过芳烃受体（AHR）/ROS 诱导的 PTEN 抑制介导的。总之，我们的结果表明，PM2.5 通过 AHR/ROS 诱导的 PTEN 抑制激活 PI3K/akt2/mTORC1 信号通路，导致线粒体介导的内在凋亡和 Wnt 信号通路抑制，从而导致斑马鱼幼虫的心脏缺陷。
