Age-dependent acrylamide neurotoxicity in mice: Morphology, physiology, and function

Acrylamide intoxication produces peripheral neuropathy characterized by wea kness and ataxia in both humans and experimental animals. Previous studies on animals of different ages and species indicate that the longest and larg est nerves are affected earlier with the major pathology in the terminal pa rts of axons, i.e., distal axonopathy However, several issues have remained elusive; for example, what are the earliest pathological changes? An equal ly intriguing question is whether younger animals are more susceptible to a crylamide than older animals. To address these issues, we compared the vuln erability to acrylamide of 3- and 8-week-old mice. These mice were intoxica ted with acrylamide in drinking water (400 ppm). The sequence of intoxicati on could be categorized into three stages. In the initial stage, there was no visible weakness or ataxia. The only noticeable changes were poor perfor mance on the rota-rod test and swelling of motor nerve terminals. Obvious w eakness and ataxia of hindlimbs developed gradually (here designated as the early stage). The weakness and ataxia progressed at variable speeds in mic e of different ages, and eventually the forelimbs (quadriparesis) were affe cted in the late stage. Each stage appeared earlier in 3-week-old mice than in 8-week-old mice (7.1 +/- 1.1 vs 15.6 +/- 4.0 days, P < 0.01 for the ear ly stage; and 15.3 +/- 2.1 vs 31.7 +/- 6.0 days,P < 0.01 for the late stage ). The progression of neurological deficits was also faster in the younger mice (7.2 +/- 1.8 vs 16.3 +/- 4.2 days, P < 0.01). Pathological changes in the distal parts of motor nerves innervating hindfoot muscles were evaluate d by combined cholinesterase histochemistry and immunocytochemistry for neu ronal markers to demonstrate motor nerve terminals and neuromuscular juncti ons simultaneously. In the initial stage, there was axonal swelling in moto r nerve terminals. As acrylamide intoxication continued, axonal swelling ex tended into junctional folds and into the intramuscular nerves, which resul ted in Wallerian-like degeneration. Our results indicate that younger mice show a much higher susceptibility to acrylamide intoxication, and pathologi cal changes precede neurological symptoms. (C) 1999 Academic Press.