N6-methyladenosine methylation mediates non-coding RNAs modification in microplastic-induced cardiac injury

Min Zhang; Jun Shi; Jun Zhou; Lei Song; Jingjing Ding; Hui Ping Deng; Li Weng; Yiqian Zhu; Zhongqing Xu

doi:10.1016/j.ecoenv.2023.115174

N6-methyladenosine methylation mediates non-coding RNAs modification in microplastic-induced cardiac injury

Ecotoxicol Environ Saf. 2023 Jun 22:262:115174. doi: 10.1016/j.ecoenv.2023.115174. Online ahead of print.

Authors

Min Zhang¹, Jun Shi², Jun Zhou³, Lei Song³, Jingjing Ding⁴, Hui Ping Deng², Li Weng⁵, Yiqian Zhu⁶, Zhongqing Xu⁷

Affiliations

¹ Division of Cardiology, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 200336 Shanghai, China. Electronic address: zm19821982@hotmail.com.
² Shanghai Institute of Pollution Control and Ecological Security, Key Laboratory of Yangtze River Water Environment Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai, China.
³ Division of Cardiology, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 200336 Shanghai, China.
⁴ Department of General Practice, Tongren Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
⁵ Department of Intervention, Tongren Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. Electronic address: yuehuiren0578@sina.com.
⁶ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: yiqianzhu@fudan.edu.cn.
⁷ Department of General Practice, Tongren Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. Electronic address: zhongqing_xu@126.com.

PMID: 37354568
DOI: 10.1016/j.ecoenv.2023.115174

Abstract

Owing to their potential adverse health effects, global contamination by microplastics (MPs) has attracted increased scientific and societal concerns. However, in vivo studies on MP toxicity, along with its effects and underlying mechanisms, remain limited. We recently found that non-coding RNA (ncRNAs) contribute to MP-mediated vascular toxicity. Moreover, previous studies have identified N6-methyladenosine (m6A) modifications in ncRNAs as influencing factors in cardiovascular disease. However, whether and how m6A modifications in ncRNAs are affected by MP-induced cardiotoxicity remain unknown. Herein, we profiled differentially expressed ncRNAs and their related m6A modification profiles in MP-exposed myocardial tissue using RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq). First, we observed that MPs accumulated in different organs and upregulated apoptosis in the heart, liver, spleen, and kidney cells. Furthermore, total m6A and METTL3 levels increased in the myocardium after exposure to MPs. RNA-seq results revealed that 392 lncRNAs and 302 circRNAs were differentially expressed in MP-treated mouse myocardium compared to the control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that these altered lncRNAs and circRNAs were closely associated with endocytosis, cellular senescence, and cell cycle signaling pathways, which may cause cardiotoxicity. Furthermore, MeRIP-seq data showed different distributions and abundances of m6A modifications in lncRNAs and circRNAs. Additionally, we identified differentially m6A methylated lncRNAs and circRNAs through conjoint analysis of the two high-throughput sequencing datasets and found that both m6A modifications and the expression of circ-Arfgef2 and lncG3bp2 were upregulated after exposure to MPs. This suggests that MP-induced m6A modifications in ncRNAs are involved in cardiotoxicity. Our findings contribute to a better understanding of MP-induced cardiotoxicity and new molecular targets for treating cardiac injury.

Keywords: Cardiotoxicity; Circ-Arfgef2; LncG3bp2; Microplastics; N6-methyladenosine.