Methyl vinyl ketone induces apoptosis in murine GT1-7 hypothalamic neurons through glutathione depletion and the generation of reactive oxygen species

Abstract

α,β-Unsaturated carbonyl compounds have been implicated in a number of environmentally-related diseases. Often, the presence of α,β-unsaturated carbonyl functionality as part of either an aliphatic or cyclic structure is considered a structural alert for cytotoxicity. We examined the cytotoxicity of methyl vinyl ketone (MVK), an aliphatic, straight-chain α,β-unsaturated carbonyl compound, in murine GT1-7 hypothalamic neurons. In addition to its widespread environmental occurrence, MVK was selected due to its extensive use in the chemical industry. Also, MVK is a close structural analog of hydroxymethylvinyl ketone that, in part, mediates the cytotoxic effects of 1,3-butadiene in vivo. It was found that MVK at low micromolar concentrations induced extensive cell death that retained key features of apoptosis such as chromatin condensation and DNA fragmentation. The MVK-induced apoptosis was associated with depletion of glutathione, disruption of mitochondrial transmembrane potential, and increased generation of reactive oxygen species (ROS). Supplementation of neuronal cells with Trolox offered partial, but significant, protection against the MVK-induced cytotoxicity, presumably due to scavenging of ROS in situ. The suggested sequence of events in the MVK-induced apoptosis in neuronal cells involves the depletion of cellular glutathione followed by an increased generation of ROS and finally the loss of mitochondrial function.