Aflatoxin B1 Induces Neurotoxicity through Reactive Oxygen Species Generation, DNA Damage, Apoptosis, and S-Phase Cell Cycle Arrest

Aflatoxin B1 (AFB(1)) is a mycotoxin widely distributed in a variety of food commodities and exhibits strong toxicity toward multiple tissues and organs. However, little is known about its neurotoxicity and the associated mechanism. In this study, we observed that brain integrity was markedly damaged in mice after intragastric administration of AFB(1)(300 mu g/kg/day for 30 days). The toxicity of AFB(1)on neuronal cells and the underlying mechanisms were then investigated in the neuroblastoma cell line IMR-32. A cell viability assay showed that the IC50 values of AFB(1)on IMR-32 cells were 6.18 mu g/mL and 5.87 mu g/mL after treatment for 24 h and 48 h, respectively. ROS levels in IMR-32 cells increased significantly in a time- and AFB(1)concentration-dependent manner, which was associated with the upregulation ofNOX2, and downregulation ofOXR1,SOD1, andSOD2. Substantial DNA damage associated with the downregulation ofPARP1,BRCA2, andRAD51was also observed. Furthermore, AFB(1)significantly induced S-phase arrest, which is associated with the upregulation ofCDKN1A,CDKN2C, andCDKN2D. Finally, AFB(1)induced apoptosis involvingCASP3andBAX. Taken together, AFB(1)manifests a wide range of cytotoxicity on neuronal cells including ROS accumulation, DNA damage, S-phase arrest, and apoptosis-all of which are key factors for understanding the neurotoxicology of AFB(1).