Manganese Neurotoxicity is Enhanced by Iron Depletion.

Abstract

Chronic exposure to manganese (Mn) results in neurobehavioral problems, particularly in children, but the molecular mechanisms are unknown. Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a significant role in neurodegenerative diseases. ER stress and the unfolded protein response (UPR) lead to cell apoptosis. Using dopaminergic SH‐SY5Y cells, we have characterized Mn cytotoxicity. Mn‐induced apoptosis was potentiated by iron depletion upon cell treatment with desferoxamine (DFO), a potent iron chelator. Mn exposure induced ER stress genes, including ER chaperone GRP94 and the pro‐apoptotic CHOP protein, with activation of ER resident caspase‐12. The important effector caspase‐3 was also activated. All of the Mn‐induced responses were enhanced by DFO treatment. To study Mn intoxication in vivo, iron‐deficient and control rats were intranasally instilled with 60 mg MnCl2/kg across 3 weeks. TUNEL staining of olfactory tissue confirmed that Mn induced apoptosis through a pathway potentiated by iron depletion. Taken together, our data reveal that Mn induces neuronal cell death through ER stress and the UPR response pathway and that this apoptotic effect is potentiated by iron deficiency. These studies provide insight into mechanisms of Mn neurotoxicity and raise awareness of the potential susceptibility of iron‐deficient children exposed to high Mn.Grant Funding Source: National Institute of Health