2. Academic Validation
  3. AHR-mediated m6A RNA methylation contributes to PM2.5-induced cardiac malformations in zebrafish larvae

AHR-mediated m6A RNA methylation contributes to PM2.5-induced cardiac malformations in zebrafish larvae

  • J Hazard Mater. 2023 Jun 2;457:131749. doi: 10.1016/j.jhazmat.2023.131749.
Cheng Ji 1,  Yizhou Tao 1,  Xiaoxiao Li 2,  Jin Wang 2,  Jin Chen 2,  Stanley Aniagu 3,  Yan Jiang 4,  Tao Chen 5
Affiliations

Affiliations

  • 1 Suzhou Medical College, Soochow University, Suzhou, China.
  • 2 Suzhou Medical College, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
  • 3 Toxicology, Risk Assessment, and Research Division, Texas Commission on Environmental Quality, 12015 Park 35 Cir, Austin, TX, USA.
  • 4 Suzhou Medical College, Soochow University, Suzhou, China. Electronic address: [email protected].
  • 5 Suzhou Medical College, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China. Electronic address: [email protected].
PMID: 37270964 DOI: 10.1016/j.jhazmat.2023.131749
Abstract

A growing body of evidence indicates that ambient fine particle matter (PM2.5) exposure inhibits heart development, but the underlying mechanisms remain elusive. We hypothesized that m6A RNA methylation plays an important role in the cardiac developmental toxicity of PM2.5. In this study, we demonstrated that extractable organic matter (EOM) from PM2.5 significantly decreased global m6A 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 m6A RNA methylation changes, which led us to focus more on the aberrant m6A 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 PM2.5 induces m6A RNA methylation changes via AHR-mediated mettl14 downregulation, which upregulates traf4a and bbc3, leading to Apoptosis and cardiac malformations.

Keywords

AHR; Heart development; M(6)A RNA methylation; PM(2.5); Zebrafish.

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