Lu Jieru, Li Zhuoyan, Ruan Xuehua, Jin Lihui, Yu Xiaogang, Zhou Xin, Zhao Jianyuan, Wu Yurong, Chen Sun, Sun Kun, Sun Jing
Department of Pediatric Cardiology, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China; Department of Pediatric, Lishui People's Hospital and The Sixth Affiliated Hospital, Wenzhou Medical University, Lishui, China; Department of Pediatric Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Department of Pediatric Cardiology, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai, China.
Comp Biochem Physiol C Toxicol Pharmacol. 2025 Oct;296:110250. doi: 10.1016/j.cbpc.2025.110250. Epub 2025 Jun 9.
Volatile organic compounds (VOCs) are widespread environmental pollutants associated with various health risks, including developmental toxicity. Our previous studies revealed a correlation between indoor VOCs exposure and an increased risk of congenital heart diseases (CHDs), which was confirmed by establishing a zebrafish exposure model. Metformin (MET), a classic hypoglycemic drug, has been identified to possess multiple properties. Based on previous research on the protective effects of metformin on air pollution, we propose a hypothesis of using metformin as protective agent against VOCs-induced developmental toxicity in zebrafish embryos and explore the underlying molecular mechanisms. The zebrafish embryos were exposed to the VOCs mixture (128 mg/L) alone or in combination with different concentrations of MET (0.5, 1.0 and 2.0 mg/mL) for 120 h. Toxicological indicators such as survival rate, hatching rate and morphological abnormalities (spinal curvature, yolk sac edema and body length reduction) were significantly alleviated by MET, especially in concentrations of 0.5 mg/mL. MET treatment effectively mitigated both cardiovascular impairments (pericardial edema and bradycardia) and neurodevelopmental deficits (locomotor activity). Transcriptomic profiling revealed MET-mediated modulation of apoptosis-related genes and cell cycle regulators. Pathway analyses identified significant enrichment in neurodevelopmental and cardiovascular functions, corroborated by acridine orange staining showing reduced apoptosis. Our findings demonstrate MET's anti-apoptotic protection against VOCs-induced developmental toxicity, suggesting its potential as a novel therapeutic intervention for pollution-related developmental disorders.
挥发性有机化合物（VOCs）是广泛存在的环境污染物，与包括发育毒性在内的各种健康风险相关。我们之前的研究揭示了室内VOCs暴露与先天性心脏病（CHD）风险增加之间的相关性，这一点通过建立斑马鱼暴露模型得到了证实。二甲双胍（MET）是一种经典的降糖药物，已被证实具有多种特性。基于之前关于二甲双胍对空气污染保护作用的研究，我们提出一个假设，即使用二甲双胍作为保护剂来对抗VOCs诱导的斑马鱼胚胎发育毒性，并探索其潜在的分子机制。将斑马鱼胚胎单独暴露于VOCs混合物（128mg/L）或与不同浓度的MET（0.5、1.0和2.0mg/mL）联合暴露120小时。MET显著减轻了诸如存活率、孵化率和形态异常（脊柱弯曲、卵黄囊水肿和体长减少）等毒理学指标，尤其是在0.5mg/mL的浓度下。MET治疗有效减轻了心血管损伤（心包水肿和心动过缓）和神经发育缺陷（运动活性）。转录组分析揭示了MET对凋亡相关基因和细胞周期调节因子的介导调节。通路分析确定了神经发育和心血管功能的显著富集，吖啶橙染色显示细胞凋亡减少，进一步证实了这一点。我们的研究结果表明MET对VOCs诱导的发育毒性具有抗凋亡保护作用，表明其作为一种针对污染相关发育障碍的新型治疗干预措施的潜力。
