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

Abstract

Aflatoxin B1 (AFB1) 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 AFB1 (300 μg/kg/day for 30 days). The toxicity of AFB1 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 AFB1 on IMR-32 cells were 6.18 μg/mL and 5.87 μg/mL after treatment for 24 h and 48 h, respectively. ROS levels in IMR-32 cells increased significantly in a time- and AFB1 concentration-dependent manner, which was associated with the upregulation of NOX2, and downregulation of OXR1, SOD1, and SOD2. Substantial DNA damage associated with the downregulation of PARP1, BRCA2, and RAD51 was also observed. Furthermore, AFB1 significantly induced S-phase arrest, which is associated with the upregulation of CDKN1A, CDKN2C, and CDKN2D. Finally, AFB1 induced apoptosis involving CASP3 and BAX. Taken together, AFB1 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 AFB1.

Chemoprotective Effects of Xanthohumol against the Carcinogenic Mycotoxin Aflatoxin B1

“…The average marginal effects, which demonstrate the effects of AFB1 (10-30 µM) on the predicted probability of each outcome (G0/G1, S, and G2/M), show that after the treatment with AFB1 (10-30 µM) the percentage of cells in the S phase was higher for 22, 30, and 25 percentage points, respectively, compared to the solvent control (0) (Figure 8B). This is consistent with previously published data reporting S-phase arrest in human bronchial epithelial cells [57], in the neuroblastoma IMR-32 cell line [58], and in HepG2 cells [59,60]. XN did not affect the cell cycle at the tested concentrations (Figure 8A,B); it also did not prevent or attenuate the AFB1-induced S phase arrest, which was confirmed by the average marginal effects on the predicted probability (Figure 8C).…”

Luteolin Alleviates AflatoxinB1-Induced Apoptosis and Oxidative Stress in the Liver of Mice through Activation of Nrf2 Signaling Pathway

“…Oxidative stress is considered to be critical molecular process underlying cell damage [ 40 ]. Oxidative stress is associated with significant increase in the generation of reactive oxygen species (ROS) while decreased antioxidant capacity in the body [ 41 ].…”

The Type 3 Deiodinase Is a Critical Modulator of Thyroid Hormone Sensitivity in the Fetal Brain

“…Both DAVID and IPA algorithms suggest E13.5 DEGs been involved in the cell cycle. In particular, upstream regulators identified by IPA indicate negative activation scores of pathways or compounds promoting transcription related to the cell cyle (RABL6, CCDN1, E2F3, E2F1, CEBPB, and aflatoxin) ( Leone et al, 1998 ; Piva et al, 2006 ; Bryant et al, 2020 ; Huang et al, 2020 ), and positive activation scores for pathways opposing cell division (TP53, asparaginase, and CDKN1A) ( Scotti et al, 2010 ; Lüdtke et al, 2013 ; Fischer et al, 2016 ; Yang et al, 2017 ). However, some genes like E2f3 and E2f1 , with primary functions regulating the cell cycle also play roles in the migration ( McClellan et al, 2007 ) and apoptosis of neurons ( Hou et al, 2000 ) and in neurogenesis ( Cooper-Kuhn et al, 2002 ).…”