Abstract
Neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, are major global health concerns and are linked to xenobiotic exposure. The rampant use of pesticides and increased number of radiological examinations can lead to neuronal alterations in the brain through oxidative stress and DNA damage. Understanding the impact of co-exposure to these agents can help identify interaction effects, enhance risk assessment, address vulnerable populations, and uncover long-term cumulative impacts that remain largely unknown. Therefore, in the current study, we aimed to explore the isolated and combined effects of low-dose radiation and malathion in the mouse brain. Mice were administered malathion (50 mg/kg) orally for 14 days, and a single whole-body low-dose radiation (0.5 Gy) on the 8th day. Five months post-exposure, behavioural, histological, enzymatic, and metabolomic analyses were carried out. Increased neuroinflammation and impaired neuronal maturation were observed in all treated groups, with neuronal death observed exclusively in the radiation group and persistent oxidative damage and acetylcholinesterase inhibition were identified in the malathion group. Additionally, the co-exposure group exhibited synergistic reductions in alpha-linoleic acid and linoleic acid metabolism, phosphatidylcholine biosynthesis, phospholipid biosynthesis, and sphingolipid metabolism within the hippocampus. Increased anxiety and reduced exploration were most pronounced in the co-exposure group, followed by the radiation group. This study provides insights into the effects of co-exposure to neurotoxicants such as low-dose radiation and malathion, revealing synergetic neuronal damage and dysregulated amino acid and lipid metabolism in the mouse hippocampus, and identifies metabolomic signatures enabling biomarker discovery and carries potential implications for the progression of neurodegeneration due to delayed systemic effects.