Resveratrol attenuates trimethyltin chloride-induced cardiac defects via the ROS/Wnt/β-catenin pathway

Trimethyltin chloride (TMT), a toxic byproduct of organotin manufacturing, is an emerging environmental contaminant linked to developmental cardiotoxicity. However, its pathogenic mechanism remains undefined. Here, using zebrafish embryos, we show that TMT exposure induced dose-dependent cardiac malformations, increasing pericardial area by 44.9 % and decreasing heart rate by 16.8 % at 5 μM (both P < 0.001), accompanied by excessive ROS (+48.5 %, P < 0.001) and mitochondrial ROS (+82.8 %, P < 0.001) generation. Co-treatment with resveratrol (RSV) or the ROS inhibitor N-acetylcysteine (NAC) reduced TMT-induced cardiac defects and suppressed ROS and mitochondrial ROS overproduction (all P < 0.05). RSV or NAC also mitigated DNA damage, mitochondrial injury, and apoptosis in the heart. Mechanistically, TMT inhibited the Wnt/β-catenin signaling pathway (-61.7 % β-catenin, P < 0.001), an effect attenuated by RSV or NAC. Inhibition of apoptosis with Ac-DEVD-CHO or activation of Wnt/β-catenin signaling with CHIR likewise alleviated TMT-induced cardiac malformations. These results indicate that TMT disrupts heart development through ROS-mediated suppression of Wnt/β-catenin signaling, leading to mitochondrial damage, DNA damage, and apoptosis. Furthermore, RSV, a dietary antioxidant, provides significant protection against TMT-induced cardiac developmental toxicity. This study identifies potential molecular targets for preventing and treating embryonic heart injury caused by environmental toxicants.