Neuropathology of skin denervation in acrylamide-induced neuropathy

Previous studies have established the neurotoxicity and pathology of acrylamide to large-diameter nerves. It remains unclear (1) whether small-diameter sensory nerves are vulnerable to acrylamide and (2) if so, how the pathology evolves during intoxication. We investigated the influence of acrylamide on small-diameter sensory nerves by studying the pathology of sensory nerve terminals in the skin. The neurotoxic effects of acrylamide (400 ppm in drinking water) on mice were assessed by immunostaining the skin with protein gene product 9.5, a ubiquitin C-terminal hydrolase, particularly useful for demonstrating cutaneous nerve terminals. Within 5 days of acrylamide administration (the initial stage), epidermal nerves showed two major changes: (1) terminal swelling and (2) increased branching. There was a progressive reduction in epidermal nerve density (END) thereafter. Fifteen days after acrylamide intoxication (the late stage), reduction in END became evident (25.22 +/- 2.19 fibers/mm vs 41.74 +/- 2.60 fibers/mm in control mice, P < 0.003). At this stage, there was significant dermal nerve degeneration with ultrastructural demonstrations of vacuolar changes. These findings establish the pathological consequences of acrylamide neurotoxicity in cutaneous sensory nerves with far-reaching implications: (1) providing an animal system to study "dying-back" pathology of nociceptive nerves and (2) forming the ultrastructural foundation for interpreting the pathology of cutaneous nerve degeneration in skin biopsies.