Dysregulation of the Hippocampal m6A-YTHDF2-Bax Axis Mediates Maternal Cadmium-Induced Neuronal Apoptosis and Cognitive Decline in Offspring

Maternal cadmium (Cd) exposure is a major environmental hazard impairing offspring neurodevelopment, but the underlying epitranscriptomic mechanisms remain elusive. Here, we identified hippocampal m6A-YTHDF2-Bax signaling axis disruption as a key link between prenatal/early postnatal Cd exposure and neurodevelopmental deficits. Utilizing a murine model that simulates environmentally relevant maternal Cd exposure, we observed elevated cerebral Cd levels and cognitive impairments in F1 offspring, which were accompanied by hippocampal neuronal apoptosis and abnormalities in synaptic ultrastructure. Mechanistically, Cd induced global m6A hypomethylation and suppressed m6A reader YTHDF2. MeRIP-seq and RNA immunoprecipitation assays confirmed Cd-reduced m6A modification of Bax mRNA and weakened YTHDF2-Bax interaction, which stabilized Bax mRNA and upregulated pro-apoptotic Bax. YTHDF2 overexpression restored Bax turnover and attenuated Cd-induced apoptosis. Collectively, these findings reveal a novel epitranscriptomic mechanism of Cd neurotoxicity and highlight YTHDF2 as a promising therapeutic target for environmentally induced neurodevelopmental disorders.