Wang_2023_Int.J.Mol.Sci_24_9938

Parkinson's disease (PD) is an increasingly common neurodegenerative movement disorder with contributing factors that are still largely unexplored and currently no effective intervention strategy. Epidemiological and pre-clinical studies support the close association between environmental toxicant exposure and PD incidence. Aflatoxin B(1) (AFB(1)), a hazardous mycotoxin commonly present in food and environment, is alarmingly high in many areas of the world. Previous evidence suggests that chronic exposure to AFB(1) leads to neurological disorders as well as cancer. However, whether and how aflatoxin B(1) contributes to the pathogenesis of PD is poorly understood. Here, oral exposure to AFB(1) is shown to induce neuroinflammation, trigger the alpha-synuclein pathology, and cause dopaminergic neurotoxicity. This was accompanied by the increased expression and enzymatic activity of soluble epoxide hydrolase (sEH) in the mouse brain. Importantly, genetic deletion or pharmacological inhibition of sEH alleviated the AFB(1)-induced neuroinflammation by reducing microglia activation and suppressing pro-inflammatory factors in the brain. Furthermore, blocking the action of sEH attenuated dopaminergic neuron dysfunction caused by AFB(1) in vivo and in vitro. Together, our findings suggest a contributing role of AFB(1) to PD etiology and highlight sEH as a potential pharmacological target for alleviating PD-related neuronal disorders caused by AFB(1) exposure.