m⁶A-Mediated Hippocampal BDNF Deficiency Contributes to Aflatoxin B1-Induced Neurotoxicity

Aflatoxin B1 (AFB1) is widely found in agricultural products. Although the neurotoxicity of AFB1 has been reported, the key molecules and underlying regulatory mechanisms remain unclear. This study demonstrates that AFB1 induces anxiety-like behavior and cognitive impairment in mice, with hippocampal transcriptomics revealing a response in neurons and astrocytes. In vitro, neurons are more sensitive to AFB1 than astrocytes, and astrocytes exposed to conditioned medium from AFB1-treated neurons mount an inflammatory response due to reduced neuronal brain-derived neurotrophic factor (BDNF) secretion. This disorder is ameliorated by exogenous BDNF administration. Mechanistically, in hippocampal neurons, AFB1 enhances m⁶A modification on the 3'UTR of BDNF mRNA, with YTHDF2 mediating the m⁶A-dependent downregulation of BDNF mRNA expression, ultimately inhibiting BDNF production. Collectively, these findings identify m⁶A modification as a regulatory target for BDNF expression, providing new insights into the mechanisms of AFB1-induced central nervous system (CNS) injury and potential therapeutic avenues.