Melatonin Prevents NaAsO2-Induced Developmental Cardiotoxicity in Zebrafish through Regulating Oxidative Stress and Apoptosis

Abstract

Melatonin is an indoleamine hormone secreted by the pineal gland. It has antioxidation and anti-apoptosis effects and a clear protective effect against cardiovascular diseases. Our previous studies demonstrated that embryonic exposure to sodium arsenite (NaAsO2) can lead to an abnormal cardiac development. The aim of this study was to determine whether melatonin could protect against NaAsO2-induced generation of reactive oxygen species (ROS), oxidative stress, apoptosis, and abnormal cardiac development in a zebrafish (Danio rerio) model. We found that melatonin decreased NaAsO2-induced zebrafish embryonic heart malformations and abnormal heart rates at a melatonin concentration as low as 10−9 mol/L. The NaAsO2-induced oxidative stress was counteracted by melatonin supplementation. Melatonin blunted the NaAsO2-induced overproduction of ROS, the upregulation of oxidative stress-related genes (sod2, cat, gpx, nrf2, ho-1), and the production of antioxidant enzymes (Total SOD, SOD1, SOD2, CAT). Melatonin attenuated the NaAsO2-induced oxidative damage, DNA damage, and apoptosis, based on malonaldehyde and 8-OHdG levels and apoptosis-related gene expression (caspase-3, bax, bcl-2), respectively. Melatonin also maintained the control levels of heart development-related genes (nkx2.5, sox9b) affected by NaAsO2. In conclusion, melatonin protected against NaAsO2-induced heart malformations by inhibiting the oxidative stress and apoptosis in zebrafish.

Phylogenetic conservation of the interdependent homeostatic relationship of sleep regulation and redox metabolism

“…It has been shown that melatonin is capable of indirectly scavenging free radicals by regulating the activity and expression of other antioxidant systems in both plant and mammals (Bidabadi et al 2020 ; Morvaridzadeh et al 2020 ; Nogués et al 2006 ). In zebrafish, like in other animals, melatonin also maintains the redox balance by regulating the ratio of reduced glutathione to oxidized glutathione (GSH/GSSG), reducing lipid peroxidation, and enhancing the activity and expression of other antioxidant enzymes such as SOD and catalase (Duarte et al 2023 ; Lunkes et al 2021 ; Yan et al 2022 ). Furthermore, melatonin administration alleviated the reduction in catalase, glutathione peroxidase and SOD activity following sleep-deprivation and enhanced GSH/GSSG ratio levels to normal (Alzoubi et al 2016 ).…”

Frontier of toxicology studies in zebrafish model

“…mechanisms, among which the observed indicators of cardiovascular toxicity were pericardial edema Maciag et al, 2022;Nie et al, 2022;Xu, Huang, et al, 2022;Yan et al, 2022;Zhu, Wang, et al, 2022;Zong et al, 2022), heart rate changes (Du et al, 2022;Fan, Yang, et al, 2022;Maciag et al, 2022;Nie et al, 2022;Xu, Huang, et al, 2022;Yan et al, 2022;Zong et al, 2022), and sinus venous-bulb arterial (SV-BA) distance changes (Chen, Qiu, et al, 2022;Du et al, 2022;Nie et al, 2022;Xu, Huang, et al, 2022;Zhu, Wang, et al, 2022), increased pericardial areas (Chen, Qiu, et al, 2022;, detailed in Table S3, Figure 3, and Figure 4. F I G U R E 3 Mechanism of cardiovascular toxic oxidative stress in zebrafish.…”

“…The zebrafish cardiovascular system begins to perform function at 24 hpf and completes heart development at 72 hpf. After the 2022 literature study on zebrafish cardiovascular toxicity, there were 14 research articles on zebrafish cardiovascular toxicity and mechanisms, among which the observed indicators of cardiovascular toxicity were pericardial edema (Huang, Wang, et al, 2022; Maciag et al, 2022; Nie et al, 2022; Xu, Huang, et al, 2022; Yan et al, 2022; Zhang, Wang, et al, 2022; Zhu, Wang, et al, 2022; Zong et al, 2022), heart rate changes (Du et al, 2022; Fan, Yang, et al, 2022; Lu, Wang, Zhang, et al, 2022; Maciag et al, 2022; Nie et al, 2022; Xu, Huang, et al, 2022; Yan et al, 2022; Zong et al, 2022), and sinus venous‐bulb arterial (SV‐BA) distance changes (Chen, Qiu, et al, 2022; Du et al, 2022; Huang, Wang, et al, 2022; Lu, Wang, Zhang, et al, 2022, Lu, Wang, Xu, et al, 2022; Nie et al, 2022; Xu, Huang, et al, 2022; Zhu, Wang, et al, 2022), increased pericardial areas (Chen, Qiu, et al, 2022; Huang, Wang, et al, 2022; Lu, Wang, Zhang, et al, 2022, Lu, Wang, Xu, et al, 2022), detailed in Table S3, Figure 3, and Figure 4. The chemical structures of the samples under related study are shown in Figure S3.…”