Drug-induced cardiotoxicity is a leading factor for drug withdrawals, and limits drug efficacy and clinical use. Therefore, new alternative animal models and methods for drug safety evaluation have been given great attention. Anthracyclines (ANTs) are widely prescribed anticancer agents that have a cumulative dose relationship with cardiotoxicity. We performed experiments to study the toxicity of ANTs in early developing zebrafish embryos, especially their effects on the heart. LC50 values for daunorubicin, pirarubicin, doxorubicin (DOX), epirubicin and DOX-liposome at 72 h post-fertilization were 122.7 μM, 111.9 μM, 31.2 μM, 108.3 μM and 55.8 μM, respectively. At the same time, zebrafish embryos were exposed to ANTs in three exposure stages and induced incomplete looping of the heart tube, pericardia edema and bradycardia in a dose-dependent manner, eventually leading to death. DOX caused the greatest heart defects in the treatment stages and its liposome reduced the effects on the heart, while daunorubicin produced the least toxicity. Genes and proteins related to heart development were also identified to be sensitive to ANT exposure and downregulated by ANTs. It revealed ANTs could disturb the heart formation and development. ANTs induced cardiotoxicity in zebrafish has similar effects in mammalian models, indicating that zebrafish may have a potential value for assessment of drug-induced developmental cardiotoxicity.

Cephalosporins, derivatives of 7-aminocephalosporanic acid (7-ACA), are potent antibacterial agents. The toxicity prediction of these compounds is of considerable importance in new drug development. Zebrafish embryo toxicity testing was thought to be suitable for evaluation of the toxic properties of cephalosporins. Here, five kinds of cephalosporins and their isomers were used for investigation of the toxic functional groups of cephalosporins and for further evaluation of the efficacy of zebrafish embryo toxicity testing. Computational chemistry methods were also used to study the conformations of the stereoisomers of cephalosporins in aqueous solution to explore the relationship between the stereoisomers and the experimental results of toxicity tests on zebrafish embryos. Our results suggest that both the C-7 and C-3 substituents of cephalosporins are toxic functional groups. The toxic functional groups increase the toxic reaction of 7-ACA and can induce variable abnormal phenotypes in zebrafish embryo toxicity testing. The embryonic toxicities of cephalosporins were involved in organogenesis, mainly in the development of the cranial nerve, cardiovascular system, notochord and abdomen, and pigment formation; those tissues and organs are derived from ectoderm, mesoderm, and endoderm. The theoretical calculations showed a strong negative correlation between topological polar surface area (TPSA) values and the toxic effect, which indicated that molecular polarity may be crucial to the toxic effects of the isomers of cephalosporins. The concept of toxic functional groups may help us understand the safety differences of cephalosporins.

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