Acrylamide (ACR) is a neurotoxic agent which produces a central-peripheral distal axonopathy. The axonopathy has occurred in humans following exposure and is induced in animals as a model for investigating pathological processes occurring in ACR-induced axonopathy as well as other primary axonopathies caused by diabetes, alcoholism, vitamin deficiencies, drugs and other neurotoxins. One proposed mechanism by which ACR produces an axonopathy involves the inhibition of enzymes responsible for ATP formation (energy hypothesis). This proposal addresses this question. More specifically: Does ACR alter oxidative metabolism responsible for energy transformations, decreasing available ATP, producing neuronal compromise and axonopathy? Assays for oxidative enzymes in control and ACR-treated cat spinal cord, peripheral nerve and liver will determine whether or not ACR inhibits these enzymes. Assays of the same enzymes, in vitro, in the presence of ACR or methylene bis acrylamide (MB ACR) will determine the specificity of enzyme inhibition. Quantitative enzyme histochemical assays in dorsal root ganglion, motor, and Purkinje neurons as well as hepatocytes of control and ACR-treated rats will be used to detect relative changes in enzyme activities of involved, single cell types. The high energy phosphate levels (ATP and CP) in peripheral nerves of chronic ACR-treated cats will be compared to controls to determine the effectiveness of enzyme inhibitions on reduction of available energy. Mitochrondria will be tested for their ability to generate ATP after ACR exposure. The association between decreased energy supplies and the neuropathy will be examined with determination of dose-dependent changes in ATP and CP and correlation of these levels with early dose-dependent changes in the rate of fast anterograde axoplasmic transport of radioactively-labelled proteins. The data obtained will contribute significantly to our knowledge of acrylamide-induced axonopathy and will lead to a continuing study of the alterations in oxidative metabolism in other toxic neuropathies.
