Disrupted Tryptophan Metabolism Mediates Manganese-Induced Neurogenesis and Neuroinflammatory Impairments: Rescue by Exogenous Melatonin

Manganese (Mn) is a common environmental pollutant, and excessive exposure can lead to motor dysfunction resembling Parkinson's disease. Increasing evidence suggests that Mn impairs endogenous neurogenesis and hinders neural repair. This study aims to investigate the effects of both acute and long-term Mn exposure on neurogenesis and to elucidate the underlying mechanisms. By establishing acute (7 and 14 days) and long-term (2 and 4 months) Mn exposure mouse models, we assessed neurogenesis under different exposure conditions. The mRNA sequencing, untargeted metabolomics, and metagenomics were employed to uncover the molecular pathways involved in Mn-induced neurogenesis impairment. The results revealed that early stage Mn exposure, including acute and 2 months exposure, transiently promoted neurogenesis. However, prolonged Mn accumulation in the brain led to suppressed neurogenesis, accompanied by neuroinflammation and oxidative stress, which contributed to a vicious cycle of neural damage. Multiomics analyses identified dysregulation of the tryptophan metabolic pathway as a key mechanism, with a marked reduction in melatonin levels following Mn exposure. Notably, exogenous melatonin supplementation effectively rescued Mn-induced impairments in neurogenesis, neuronal integrity, and neuroinflammation. These findings provide new insights into Mn neurotoxicity and highlight melatonin as a potential therapeutic agent for Mn-related neural damage.