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

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.

• Authors: Liang Xiong, Jinyu Huang, Sihui Wang, Qiong Yuan, Dongmei Yang, Zuobing Zheng, Yangna Wu, Chunmei Wu, Yanfang Gao, Lijun Zou, Gonghua Hu
• Journal: Archives of toxicology (Arch Toxicol) Vol. 96 Issue 3 Pg. 767-781 (03 2022) ISSN: 1432-0738 [Electronic] Germany
• PMID: 35088107 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Antioxidants
• NF-E2-Related Factor 2
• Nfe2l2 protein, rat
• PPAR gamma
• Reactive Oxygen Species
• yttrium chloride
• Yttrium

Topics

• Animals
• Antioxidants (metabolism)
• Cardiotoxicity (etiology)
• Cell Line
• DNA Damage (drug effects)
• Myocytes, Cardiac (drug effects, pathology)
• NF-E2-Related Factor 2 (metabolism)
• PPAR gamma (metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Yttrium (toxicity)