Veratramine induces cardiac developmental defects in zebrafish embryos via regulating the Wnt signaling pathway

Cancer and cardiovascular diseases represent leading chronic threats to human health, with pharmacotherapy serving as the primary intervention for both. Plant-derived bioactive compounds have emerged as vital sources of antineoplastic agents. Veratramine (VEM), a naturally occurring plant steroidal alkaloid, is widely used in medicine and agriculture. Assessing the toxicity of natural compounds to living organisms is crucial, given the pivotal role of the cardiovascular system in maintaining physiological homeostasis. Nevertheless, the potential toxicity of natural compounds to this vital system remains poorly understood. Herein, we used zebrafish as a model system to evaluate the effects of VEM on cardiac development. Our results demonstrated that VEM impairs zebrafish larval development, with cardiovascular toxicity manifested as yolk sac edema, pericardial edema, increased heart size, reduced atrial-ventricular overlap, increased distance between the sinus venosus and bulbus arteriosus, abnormal cardiac looping, cardiac ejection disorders, and decreased heart rate. Specifically, VEM dysregulates the expression of genes involved in cardiac development, induces oxidative stress in the cardiac region of zebrafish larvae, and triggers cardiomyocyte apoptosis and abnormal proliferation, ultimately leading to cardiac injury. Furthermore, our study is the first to show that VEM exposure activates the Wnt/β-catenin pathway and treatment with a Wnt signaling inhibitor rescues VEM-induced cardiac developmental defects. Taken together, our findings indicate that VEM induces cardiac developmental defects in zebrafish larvae by inducing oxidative stress and activating the Wnt/β-catenin pathway.