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Yttrium chloride-induced cytotoxicity and DNA damage response via ROS generation and inhibition of Nrf2/PPARγ pathways in H9c2 cardiomyocytes

  • Inorganic Compounds
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Abstract

Increasing exploration of rare-earth elements (REEs) has resulted in a high REEs’ exposure risk. Owing to their persistence and accumulation of REEs in the environment, their adverse effects have caused widespread concern. However, limited toxicological data are available for the adverse effects of yttrium (Y) and its underlying mechanisms of action. In the present study, H9c2 cardiomyocytes were used in vitro model to investigate the cardiotoxicity of yttrium chloride (YCl3). Results show that YCl3 treatment resulted in reactive oxygen species (ROS) overproduction, decrease in ∆Ψm, and DNA damage. Mechanistically, we detected expression levels of protein in response to cellular DNA damage and antioxidative defense. Results indicated that the phosphorylation of histone H2AX remarkably increased in a dose-dependent manner. At a high YCl3-exposure concentration (120 μM), specific DNA damage sensors ATM/ATR-Chk1/Chk2 were significantly decreased. The protein levels of key antioxidant genes Nrf2/PPARγ/HO-1 were also remarkably inhabited. Additionally, the antioxidant N-acetyl-l-cysteine (NAC) pretreatment promoted the activation of antioxidative defense Nrf2/PPARγ signaling pathways, and prevented the production of cellular ROS, thus protecting the DNA from cleavage. Altogether, our findings suggest that YCl3 can induce DNA damage through causing intracellular ROS overproduction and inhibition of antioxidative defense, leading to cytotoxicity in H9c2 cardiomyocytes.

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Abbreviations

ATM:

Ataxia telangiectasia mutated

ATR:

Ataxia telangiectasia mutated and Rad3-related

Bax:

Bcl-2 associated X

Bcl-2:

B-cell lymphoma-2

Caspase-3:

Cysteine aspartate-specific protease 3

CCK-8:

Cell counting kit-8

Chk1:

Checkpoint kinase 1

Chk2:

Checkpoint kinase 2

DAPI:

4',6-Diamidino-2-phenylindole

DCFH-DA:

2′,7′-Dichlorofluorescin diacetate

DDR:

DNA damage response

Fpg:

Formamidopyrimidine DNA glycosylase

HO-1:

Heme oxygenase-1

JC-1:

5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide

LC50 :

The median lethal concentration

MDA:

Malondialdehyde

GSH:

Glutathione

NAC:

N-Acetyl-cysteine

Nrf2:

Nuclear factor erythroid 2-related factor 2

PPARγ:

Peroxisome proliferator-activated receptor γ

REEs:

Rare-earth elements

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

γ-H2AX:

Phosphorylation of histone H2AX at Ser139

∆Ψm:

Mitochondrial membrane potential

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81460504 and 81960599), the Science and Technology Project funded by the Education Department of Jiangxi Province (GJJ150940 and GJJ201525), the Open Project of Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education (XN201901 and XN202028), the Project of Scientific and Technological Innovation Team of Gannan Medical University (TD201801), and the Doctor Initial Funding for Gannan Medical University (QD201503).

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Authors and Affiliations

  1. Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, Jiangxi, China

    Liang Xiong, Jinyu Huang, Zuobing Zheng, Chunmei Wu, Yanfang Gao & Gonghua Hu

  2. School of Public Health and Health Management, Gannan Medical University, Ganzhou, 341000, Jiangxi, China

    Liang Xiong, Sihui Wang, Qiong Yuan, Dongmei Yang, Yangna Wu, Chunmei Wu, Yanfang Gao, Lijun Zou & Gonghua Hu

  3. Department of Anatomy, School of Basic Medicine Sciences, Gannan Medical University, Ganzhou, 341000, Jiangxi, China

    Jinyu Huang

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  1. Liang Xiong
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Xiong, L., Huang, J., Wang, S. et al. Yttrium chloride-induced cytotoxicity and DNA damage response via ROS generation and inhibition of Nrf2/PPARγ pathways in H9c2 cardiomyocytes. Arch Toxicol 96, 767–781 (2022). https://doi.org/10.1007/s00204-022-03225-1

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