Nerve terminals as the primary site of acrylamide action: a hypothesis

Abstract

Acrylamide (ACR) is considered to be prototypical among chemicals that cause a central-peripheral distal axonopathy. Multifocal neurofilamentous swellings and eventual degeneration of distal axon regions in the CNS and PNS have been traditionally considered the hallmark morphological features of this axonopathy. However, ACR has also been shown to produce early nerve terminal degeneration of somatosensory, somatomotor and autonomic nerve fibers under a variety of dosing conditions. Recent research from our laboratory has demonstrated that terminal degeneration precedes axonopathy during low-dose subchronic induction of neurotoxicity and occurs in the absence of axonopathy during higher-dose subacute intoxication. This relationship suggests that nerve terminal degeneration, and not axonopathy, is the primary or most important pathophysiologic lesion produced by ACR. In this hypothesis paper, we review evidence suggesting that nerve terminal degeneration is the hallmark lesion of ACR neurotoxicity, and we propose that this effect is mediated by the direct actions of ACR at nerve terminal sites. ACR is an electrophile and, therefore, sulfhydryl groups on presynaptic proteins represent rational molecular targets. Several presynaptic thiol-containing proteins (e.g. SNAP-25, NSF) are critically involved in formation of SNARE (soluble N-ethylmaleimide (NEM)-sensitive fusion protein receptor) complexes that mediate membrane fusion processes such as exocytosis and turnover of plasmalemmal proteins and other constituents. We hypothesize that ACR adduction of SNARE proteins disrupts assembly of fusion core complexes and thereby interferes with neurotransmission and presynaptic membrane turnover. General retardation of membrane turnover and accumulation of unincorporated materials could result in nerve terminal swelling and degeneration. A similar mechanism involving the long-term consequences of defective SNARE-based turnover of Na+/K(+)-ATPase and other axolemmal constituents might explain subchronic induction of axon degeneration. The ACR literature occupies a prominent position in neurotoxicology and has significantly influenced development of mechanistic hypotheses and classification schemes for neurotoxicants. Our proposal suggests a reevaluation of current classification schemes and mechanistic hypotheses that regard ACR axonopathy as a primary lesion.