2. Academic Validation
  3. Lethal toxicity of metformin on zebrafish during early embryonic development by multi-omics analysis

Lethal toxicity of metformin on zebrafish during early embryonic development by multi-omics analysis

  • Sci Rep. 2025 Apr 2;15(1):11309. doi: 10.1038/s41598-025-95816-y.
Ziyuan Lin 1 2 3,  Mingfeng Liu 1 2,  Feng Chen 1 2,  Chanjuan Zhao 2,  Yanyan Liu 4 5,  Huaqin Sun 6 7 8
Affiliations

Affiliations

  • 1 SCU-CUHK Joint Laboratory for Reproductive Medicine, Zebrafish Research Platform, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 2 Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, Sichuan, China.
  • 3 Children's Medicine Key Laboratory of Sichuan Province, Chengdu, China.
  • 4 Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. liuyy39@qq.com.
  • 5 Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, Sichuan, China. liuyy39@qq.com.
  • 6 SCU-CUHK Joint Laboratory for Reproductive Medicine, Zebrafish Research Platform, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. sunhuaqin@scu.edu.cn.
  • 7 Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, Sichuan, China. sunhuaqin@scu.edu.cn.
  • 8 Children's Medicine Key Laboratory of Sichuan Province, Chengdu, China. sunhuaqin@scu.edu.cn.
PMID: 40175592 DOI: 10.1038/s41598-025-95816-y
Abstract

Metformin is an antidiabetic drug used in type 2 diabetes as well as indicators in polycystic ovary syndrome (PCOS) and Cancer. Due to their increase in popularity, high amounts of metformin are being released into aquatic environments. However, the toxic effect of metformin on embryonic development in aquatic organisms remains limited. Therefore, this study aimed to elucidate the lethal embryotoxicity of metformin and determine the underlying molecular pathways influencing embryonic development using a zebrafish model through multi-omics analysis. Metformin was microinjected into zebrafish embryos at the 1-cell stage with varying concentrations (50 mM, 100 mM, 200 mM, 400 mM, and 800 mM). From the results, hatching rates decreased in a dose dependent manner. Fetal malformation and mortality (LC50 = 339.8 mM) increased in a dose dependent manner. In situ hybridization of whole-embryo assays demonstrated that metformin exerts a significant impact on the initial stages of embryonic development, leading to aberrant differentiation of the germ layers, perturbed organogenesis, and delayed development. Furthermore, transcriptomics, metabolomics, and lipidomics were used to study the molecular mechanisms of embryonic toxicity. The results showed that the cell cycle, dorsoventral axis formation, and collecting duct acid secretion pathways were significantly altered in treated embryos. In brief, these results provide useful information on the lethal toxicity mechanism of metformin overdose and provide clues for further studies in humans.

Figures
Products