Early-life manganese overexposure induces dysfunction in energy metabolism conversion that leads to disrupted hippocampal neurogenesis in mouse offspring via METTL3-mediated Cdc25b m6A modification
- J Hazard Mater. 2026 Jun 13:514:142703. doi: 10.1016/j.jhazmat.2026.142703.
- 1. Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, China Medical University, Ministry of Education, Shenyang, Liaoning 110122, China; Department of Health Statistics, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, China.
- 2. Program of Environment Physical Factors and Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, China; Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110000, China.
- 3. Program of Environment Physical Factors and Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, China.
- 4. Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, China Medical University, Ministry of Education, Shenyang, Liaoning 110122, China; Program of Environment Physical Factors and Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, China.
- 5. Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, China Medical University, Ministry of Education, Shenyang, Liaoning 110122, China; Program of Environment Physical Factors and Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, China. Electronic address: [email protected].
Early-life manganese (Mn) overexposure induces cognitive flexibility impairments by disrupting hippocampal neurogenesis and decreasing neural stem cells (NSCs) differentiation into neuroblasts. CDC25B is a key regulator required for both the cell cycle and NSCs differentiation. However, the association between energy metabolism conversion and Mn-related hippocampal neurogenesis malfunction, and whether this malfunction is caused by Cdc25b mRNA decay, remains unclear. This study utilized C57BL/6 mouse offspring and applied single-cell RNA Sequencing to investigate the link between Mn-induced cognitive impairment and early-life neurogenesis disruption. The results showed that 1.1 mg/kg/day Mn exposure significantly impaired cognitive flexibility. This impairment was associated with disrupted NSCs differentiation into neuroblasts. Subsequently, we used primary NSCs to examine whether disrupted energy metabolism conversion affected METTL3-mediated Cdc25b mRNA decay. Aligned with this hypothesis, NSCs exposed to 50 μM Mn showed an unsuccessful transition from glycolysis to OXPHOS and an elevated METTL3-dependent Cdc25b m6A modification, which led to reduced mRNA stability. In conclusion, Mn-associated inhibition of energy metabolism conversion in NSCs interrupts the CDC25B-regulated NSCs differentiation into neuroblasts in hippocampal neurogenesis.