ROLE OF CALCIUM IN ACRYLAMIDE NEUROTOXICITY

Chronic exposure to acrylamide causes skeletal muscle weakness associated with a distal axonopathy. The biochemical lesion responsible for this neuronal damage has not been identified. Recent research indicates that an increase in intraneuronal calcium induced by a variety of injurious processes (e.g. chemical, disease) is responsible for the resulting neuronal damage and/or death. Thus, acrylamide might produce injury by causing cellular membranes to become "leaky" thereby allowing an influx of extracellular calcium and other ions. The resulting increase in cytoplasmic calcium could cause nerve cell injury by inhibiting mitochondrial respiration, by disrupting cytoskeletal structure or by a direct inhibition of axonal transport. The proposed investigation will determine whether a progressive increase in the concentration of calcium is temporally related to acrylamide intoxication. These studies will involve the use of nervous tissues from acrylamide-treated rats and nerve cell culture systems exposed to this neurotoxin. Specifically, initial studies will employ atomic absorption spectrophotometry to measure acrylamide-induced changes in total calcium concentrations. Changes in calcium levels will be correlated temporally with the development of neuronal damage caused by acrylamide. Autoradiography (45Ca) will be used to identify nuclei or regions in brains from acrylamide-treated rats which exhibit changes in calcium uptake and/or retention. Such areas (e.g. cerebellum) might represent structures which are selectively damaged by acrylamide and therefore are importantly involved in the manifestation of neurotoxicity. Alterations in the subcellular distribution of calcium and other ions produced by acrylamide will be determined using x-ray microanalysis. With this technique it is possible to measure ion concentrations in mitochondria and other subcellular organelle. Acrylamide neurotoxicity might be mediated by the inhibitory effect of calcium on mitochondrial respiration. Therefore, oxygen uptake will be measured using a Clark's oxygen electrode in nervous tissues and in nerve cell cultures exposed to acrylamide. The long range goal of this research is to identify the role of calcium in the distal axonpathy produced by acrylamide and other neurotoxins. Results from this research might implicate an involvement of calcium in human disease states (e.g. infantile neuroaxonal dystrophy) which are associated with neuropathic changes similar to those induced by acrylamide.