Acrylamide-regulated neurofilament expression in rat pheochromocytoma cells

Using the rat pheochromocytoma cell line (PC12), we present molecular evide nce that the neurotoxicant acrylamide directly induces neurofilament gene e xpression, and the signaling pathways are initially distinctive from, but e ventually merged into, that for nerve growth factor (NGF)-induced neurofila ment expression. In PC12 cells, acrylamide increased neurofilament protein levels and synthesis. Acrylamide had no effect on the stability of neurofil ament mRNAs suggesting that it directly increased neurofilament mRNA synthe sis. K252a, a selective inhibitor for NGF receptor gp140trk, had no effect on acrylamide induction, but completely inhibited NGF-induced neurofilament protein synthesis. Therefore, the initial step for acrylamide signaling wa s distinctive from NGF. Dexamethasone reversed the effects of both NGF and acrylamide on neurofilament protein levels and synthesis indicated that the re is a dexamethasone-sensitive signaling step upon which NGF and acrylamid e merge, suggesting involvement of transcription-activating proteins like A P-1. These results, taken together with previous studies of transgenic mice that overexpress neurofilament genes, may partially explain the mechanisms of neurofilament accumulation in distal parts of large axons, a pathognomo nic feature of acrylamide neurotoxicity in animals. (C) 2000 Published by E lsevier Science B.V. All rights reserved.