Synergistic neurotoxic effects of arsenic and dopamine in human dopaminergic neuroblastoma SH-SY5Y cells

Abstract

Parkinson's disease is an environmentally influenced, neurodegenerative disease of unknown origin that is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Arsenic is an environmental contaminant found naturally in ground water, industrial waste, and fertilizers. The initial goal of the present study was to determine if a mixture of arsenite (As+3) and dopamine (DA) could cause enhanced degeneration of dopaminergic neuronal cells. Additional goals were to determine the mechanism (apoptosis or necrosis) of As- and DA-induced cell death and if death could be attenuated by antioxidants. The cell culture model employed was the SH-SY5Y neuroblastoma cell line that has been shown to possess differentiated characteristics of dopaminergic neurons. The results demonstrated that a mixture of As+3 and DA was synergistic in producing the death of the SH-SY5Y cells when compared with exposure to either agent alone. A mixture of 10 μM As+3 and 100 μM DA produced almost a complete loss of cell viability over a 24-h period of exposure, whereas, each agent alone had minimal toxicity. It was shown that necrosis, and not apoptosis, was the mechanism of cell death produced by exposure of the SH-SY5Y cells to the mixture of As+3 and DA. It was also demonstrated that the antioxidants, N-acetylcysteine, and Sulforaphane, attenuated the toxicity of the mixture of As+3 and DA to the SH-SY5Y cells. This study provides initial evidence that As+3 and DA synergistically can cause enhanced toxicity in cultured neuronal cells possessing dopaminergic differentiation. © The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.