Developmental Toxicity Of Auranofin In Zebrafish Embryos

Toxicity is one of the major reason for failure in drug development.Auranofin(AF)is used in clinic for the treatment of rheumatoid arthritis,repurposing of AF as an anticancer drug has just finished a phase ?/? clinical trial,but the developmental toxicity of AF remains obscure.Method:This study focused on its developmental toxicity by using zebrafish embryos.Zebrafish embryos were exposed to different concentrations(1.0,2.5,5.0,10.0 ?M)of AF from 2 hours post-fertilization(hpf)to 72 hpf.At 72 hpf,two major developmental defects caused by AF were found,namely severe pericardial edema and hypopigmentation,when embryos were exposed to concentrations high than 2.5?M.Biochemical detection of oxidative stress enzyme combined with expressions of a series of genes related to oxidative stress,cardiac,metal stress,and pigment formation were subsequently tested.Result:The SOD activity was decreased while MDA content was accumulated by AF treatment.The expression of oxidative stress-related genes(sodl,gpxla,gst),pigment-related genes(mitfb,trp-1a)and one metal stress-related gene Ctrl were all decreased by AF exposure.The expressions of cardiac-related genes(amhc,vmhc)and one metal-related gene hsp70 were found to be significantly upregulated by AF exposure.These findings indicated the potential developmental toxicity of AF on zebrafish early development.Objective:By examine the results,this study attempts to assess the developmental toxicity of AF and give evidence for its future safety use in clinic.