N6-methyladenosine demethylase FTO regulates neuronal oxidative stress via YTHDC1-ATF3 axis in arsenic-induced cognitive dysfunction.

Autor: Zhou L; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Li R; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Wang F; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Zhou R; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Xia Y; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Jiang X; Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing 400016, China., Cheng S; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Wang F; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Li D; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Zhang J; Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China., Mao L; Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China., Cai X; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Zhang H; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China; Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Qiu J; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China; Department of Health Laboratory Technology, School of Public Health, Chongqing Medical University, Chongqing 400016, China., Tian X; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: xintian@cqmu.edu.cn., Zou Z; Molecular Biology Laboratory of Respiratory Disease, Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China. Electronic address: zouzhen@cqmu.edu.cn., Chen C; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China; Research Center for Environment and Human Health, Chongqing Medical University, Chongqing 400016, China. Electronic address: chengzhichen@cqmu.edu.cn.
Jazyk: angličtina
Zdroj: Journal of hazardous materials [J Hazard Mater] 2024 Dec 05; Vol. 480, pp. 135736. Date of Electronic Publication: 2024 Sep 04.
DOI: 10.1016/j.jhazmat.2024.135736
Abstrakt: Excessive exposure to metals in daily life has been proposed as an environmental risk factor for neurological disorders. Oxidative stress is an inevitable stage involved in the neurotoxic effects induced by metals, nevertheless, the underlying mechanisms are still unclear. In this study, we used arsenic as a representative environmental heavy metal to induce neuronal oxidative stress and demonstrated that both in vitro and in vivo exposure to arsenic significantly increased the level of N6-methyladenosine (m6A) by down-regulating its demethylase FTO. Importantly, the results obtained from FTO transgenic mice and FTO overexpressed/knockout cells indicated that FTO likely regulated neuronal oxidative stress by modulating activating transcription factor 3 (ATF3) in a m 6 A-dependent manner. We also identified the specific m6A reader protein, YTHDC1, which interacted with ATF3 and thereby affecting its regulatory effects on oxidative stress. To further explore potential intervention strategies, cerebral metabolomics was conducted and we newly identified myo-inositol as a metabolite that exhibited potential in protecting against arsenic-induced oxidative stress and cognitive dysfunction. Overall, these findings provide new insights into the importance of the FTO-ATF3 signaling axis in neuronal oxidative stress from an m 6 A perspective, and highlight a beneficial metabolite that can counteract the oxidative stress induced by arsenic.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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