Dyshomeostasis of iron and its transporter proteins in cypermethrin-inducedParkinson’s disease

Abstract

Abstract The aetiology of Parkinson’s disease (PD) is highly complex and is still indefinable. However, a number of studies have indicated the involvement of pesticides and transition metals. Copper, magnesium, iron and zinc haveemerged asimportantmetal contributors. Exposure to pesticides cause an accumulation of transition metals in the substantia nigra (SN) region of brain. Cypermethrin model of PD is characterized with mitochondrial dysfunction, autophagy impairment, oxidative stress, etc. However, the effect of cypermethrin on metal homeostasis is not yet explored. The study was designed to delineate the role of metals and their transporter proteins in cypermethrin-induced animal and cellular models of PD. Level of copper, magnesium, iron and zinc waschecked in the nigrostriatal tissue and serum by atomic absorption spectroscopy. Since cypermethrin consistently increased iron content in the nigrostriatal tissue and serum after 12 weeks of exposure, level of iron transporter proteins, such asdivalent metal transporter-1 (DMT-1), ceruloplasmin, transferrin, ferroportin and hepcidin and their in silico interaction with cypermethrin were checked. 3,3′-Diaminobenzidine-enhanced Perl’s staining showed anelevated number of iron positive cells in the SN of cypermethrin-treated rats. Molecular docking studies revealed a strong binding affinity between cypermethrin and iron transporter protein receptors of human andrat. Furthermore, cypermethrin increased the expression of DMT-1 and hepcidin while reduced the expression of transferrin, ceruloplasmin and ferroportin in the nigrostriatal tissue and human neuroblastoma cells. These observations suggest that cypermethrin alters the expression of iron transporter proteins leading to iron dyshomeostasis, which could contribute to dopaminergic neurotoxicity.