PM2.5 induces cardiac malformations via PI3K/akt2/mTORC1 signaling pathway in zebrafish larvae*

被引:13
|
作者
Jiang, Yan [1 ]
Zhao, Xiahao [1 ]
Chen, Jin [1 ]
Aniagu, Stanley [3 ]
Chen, Tao [1 ,2 ,4 ]
机构
[1] Soochow Univ, Suzhou Med Coll, Suzhou, Peoples R China
[2] Soochow Univ, Jiangsu Key Lab Prevent & Translat Med Geriatr Dis, Suzhou, Peoples R China
[3] Texas Commiss Environm Qual, Toxicol Risk Assessment & Res Div, 12015 Pk 35 Cir, Austin, TX USA
[4] Soochow Univ, 199 Ren Ai Rd, Suzhou 215123, Peoples R China
关键词
PM2; 5; Heart development; akt2; Apoptosis; Wnt signaling; Zebrafish; DEVELOPMENTAL TOXICITY; MAMMALIAN TARGET; MTOR; APOPTOSIS; ACTIVATION; RAPAMYCIN; CANCER; LEADS; PTEN; AHR;
D O I
10.1016/j.envpol.2023.121306
中图分类号
X [环境科学、安全科学];
学科分类号
08 ; 0830 ;
摘要
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 beta-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/ROSinduced PTEN suppression, which leads to mitochondrial-mediated intrinsic apoptosis and Wnt signaling suppression, resulting in cardiac defects in zebrafish larvae.
引用
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页数:8
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