Ticlopidine induces cardiotoxicity in zebrafish embryos through AHR-mediated oxidative stress signaling pathway

• Published in: Ecotoxicology and environmental safety Vol. 230; p. 113138
• Main Authors: Xu, Rong, Huang, Yong, Lu, Chen, Lv, Weiming, Hong, Shihua, Zeng, Shuqin, Xia, Wenyan, Guo, Li, Lu, Huiqiang, Chen, Yijian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.01.2022; Elsevier
• Subjects: Aromatic hydrocarbon receptor inhibitor; Cardiotoxicity; Heart failure; Oxidative stress; Ticlopidine; Heart failure; Oxidative stress; Cardiotoxicity; Aromatic hydrocarbon receptor inhibitor; Ticlopidine
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2021.113138

Ticlopidine has inhibitory effects on platelet aggregation via ADP (adenosine diphosphate), platelet release reaction and depolymerization. In clinical practice, it is commonly used to prevent heart, cerebrovascular and other thromboembolic diseases. However, ticlopidine has also been reported to have teratogenic effects on the heart, though its specific molecular mechanism remains unclear. In this study, zebrafish embryos were used as model organisms to examine the toxicity effect of ticlopidine. Zebrafish embryos exposed to 6, 7.5, and 9 mg/L ticlopidine solutions manifested several abnormalities, including body curvature, smaller eyes, slower absorption of the vitella sac, pericardial edema, slower heart rate, increased mortality, longer venous sinus - arterial ball (SV-BA) distance, and increased oxidative stress, which indicated developmental and cardiac toxicity. Abnormal expression of key genes related to heart development was observed, and the level of apoptotic gene expression was up-regulated. Further experiments revealed up-regulation of embryonic oxidative stress following ticlopidine exposure, leading to a decrease in cardiomyocyte proliferation. Conversely, the aromatic hydrocarbon receptor (AHR) inhibitor CH223191 protected embryos from the cardiotoxicity effect of ticlopidine, confirming further the role of up-regulated oxidative stress as the molecular mechanism of ticlopidine-induced cardiotoxicity in zebrafish. In conclusion, ticlopidine exposure leads to developmental and cardiotoxicity in zebrafish embryos. Therefore, further studies are warranted to ascertain such potential harms of ticlopidine in humans, which are vital in providing guidance in the safe use of drugs in clinical practice. •Ticlopidine affects early cardiac development in zebrafish, causing cardiac damage and cardiotoxicity.•Ticlopidine exposure increases oxidative stress and induces a decrease in zebrafish cardiomyocyte proliferation.•The cardiac developmental toxicity induced by ticlopidine is associated with oxidative stress.•The aromatic hydrocarbon receptor (AHR) inhibitor CH223191 can rescue the phenotype caused by ticlopidine exposure.