LAUSR

HIGHLIGHTSRepeated Mn injection produced motor deficit and non‐motor dysfunction.Mn administration activated microglia and produced dopamine neuron loss.Mn administration disrupted circadian clock gene expression in the brain and liver.Mn decreased expression of circadian clock core genes and feedback control genes.Circadian clock targeted genes in the liver were increased by Mn. ABSTRACT Manganese (Mn) neurotoxicity displays non‐motor dysfunction and motor impairment like Parkinson's disease (PD), and is called as Manganism. Circadian disruption is a non‐motor symptom found in PD and Manganism. Clock genes are essential to drive and maintain circadian rhythm, but little is known about Mn exposure on circadian clock genes expression. Both the brain and liver are targets of Mn, we hypothesize that repeated Mn administration could affect clock gene expression in the hypothalamus and livers. Male Sprague‐Dawley rats were intraperitoneally injected Mn2+ 1 mg and 5 mg/kg as MnCl2·4H2O, every other day for 30 days. Mn neurotoxicity was evaluated by behavioral changes and loss of dopaminergic neurons via immunohistochemistry. The expression of circadian clock genes was determined via RT‐qPCR. Repeated Mn administration dose‐dependently retarded the body weight gain, impaired the rotarod activity, decreased the number of dopaminergic neurons in the substantia nigra, and activated microglia in the brain. Expressions of circadian core genes brain and muscle Arnt‐like protein‐1 (Bmal1), locomotor output cycles kaput (Clock) and neuronal PAS domain protein2 (Npas2), and clock feedback gene cryptochrome1 (Cry1), period genes (Per1 and Per2) in the hypothalamus and liver were decreased after exposure to Mn in a dose‐dependent manner, while expressions of clock‐targeted genes nuclear receptor Rev‐Erb&agr; (Nr1d1) and D‐box‐binding protein (Dbp) were increased. Peripheral clock in the liver appears to be more susceptible to Mn‐induced abnormal clock gene expression. In summary, repeated Mn administration produced dysregulation of circadian clock gene expressions in both the brain and liver.