A systematic toxicity evaluation of cephalosporins via transcriptomics in zebrafish and in silico ADMET studies

Cephalosporins are beta-lactam antibiotics that are widely used in clinics in China. However, information on their toxicity to zebrafish is limited. This study reports that the toxicity effects of cephalosporins containing an N-methyltetrazolthio ring at the C-3 position (CNMTs) exposure on zebrafish were comparable to those predicted by in silico analysis. The effects of CNMTs on the mortality and malformation rate of zebrafish were concentration-dependent. The transcriptional levels of the has1 and cnnm2a genes, which are related to embryo development and absorption of Mg2+ in vivo, significantly changed. Several pathways that were enriched by differentially expressed genes (DEGs) were identified, and the most significantly co-enriched pathways were related to neuroactive ligand-receptor interactions, cardiac muscle contraction, and vascular smooth muscle contraction. In sum, the C-3 substituent in the nucleus 7-aminocephalosporanic acid (7-ACA) of CNMTs is responsible for the observed toxicity at higher concentrations, and the C-7 substituent plays an important role in toxicity at lower concentrations. Our results show that zebrafish embryos and transcriptomics may be useful for determining target organ toxicity, assessing the structure and toxicity relationship of chemicals, and improving drug safety assessments.