Metformin has been widely detected in aquatic ecosystems, yet the knowledge of its impact on aquatic organisms, particularly at environmentally relevant concentrations, remains limited. In the present study, we characterized the developmental toxicity of metformin in zebrafish, utilizing a transcriptome-guided toxicological assessment framework. Transcriptomic analysis conducted at metformin concentrations within the μg/L range revealed significant disruptions in biological processes associated with nucleotide, hydrocarbon, and amino acid metabolism, suggesting a significant disturbance in energy homeostasis. This observation was corroborated by energy-targeted metabolomic analysis, wherein a considerable number of metabolites involved in purine metabolism, pyrimidine metabolism, and the citrate cycle displayed significant alterations. Notably, most intermediates in the citrate cycle such as acetyl-CoA exhibited remarkable decreases. Additionally, our study identified significant impediments in zebrafish embryonic development, including decreased yolk extension progress, spontaneous contraction and body length, and increased yolk sac area and yolk/while body lipid content ratio, at metformin concentrations as low as 0.12 μg/L. Furthermore, the disruption of energy homeostasis by metformin was observed to persist into adulthood even after a prolonged recovery period. The present findings highlighted the disruptive effects of metformin on energy homeostasis and embryonic development in teleost at environmentally relevant concentrations, thereby prompting a reevaluation of its environmental risk to nontarget aquatic organisms.

中文翻译：

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转录组指导的二甲双胍环境毒性表征：在环境相关浓度下破坏能量稳态和抑制斑马鱼胚胎发育


二甲双胍已在水生生态系统中广泛检测到，但对其对水生生物的影响，特别是在与环境相关的浓度下的影响，其了解仍然有限。在本研究中，我们利用转录组指导的毒理学评估框架表征了二甲双胍在斑马鱼中的发育毒性。在 μg/L 范围内的二甲双胍浓度下进行的转录组学分析显示，与核苷酸、碳氢化合物和氨基酸代谢相关的生物过程受到显著干扰，表明能量稳态存在显著干扰。这一观察结果得到了能量靶向代谢组学分析的证实，其中参与嘌呤代谢、嘧啶代谢和柠檬酸盐循环的大量代谢物显示出显着变化。值得注意的是，柠檬酸盐循环中的大多数中间体（如乙酰辅酶 A）表现出显着的减少。此外，我们的研究发现了斑马鱼胚胎发育的重大障碍，包括蛋黄延伸进度减慢、自发收缩和体长，以及蛋黄囊面积和蛋黄/同时脂质含量比增加，二甲双胍浓度低至 0.12 μg/L。此外，观察到二甲双胍对能量稳态的破坏即使在漫长的恢复期后仍持续到成年。目前的研究结果强调了二甲双胍在环境相关浓度下对硬骨能量稳态和胚胎发育的破坏性影响，从而促使重新评估其对非目标水生生物的环境风险。