Elsevier

NeuroToxicology

Volume 24, Issue 1, January 2003, Pages 125-136
NeuroToxicology

Acrylamide Neuropathy: III. Spatiotemporal Characteristics of Nerve Cell Damage in Forebrain

https://doi.org/10.1016/S0161-813X(02)00155-9Get rights and content

Abstract

Previous studies of acrylamide (ACR) neuropathy in rat PNS [Toxicol. Appl. Pharmacol. (1998) 151: 211–221] and in spinal cord, brainstem and cerebellum [NeuroToxicology (2002a) 23: 397–414; NeuroToxicology (2002b) 23: 415–429] have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To conclude our studies of neurodegeneration in rat CNS during ACR neurotoxicity, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal argyrophilia in forebrain regions and nuclei. Rats were exposed to ACR at a dose-rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.) and at selected times brains were removed and processed for silver staining. Results show that intoxication at either ACR dose-rate produced a terminalopathy, i.e. nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the higher ACR dose-rate caused early onset (day 5), widespread nerve terminal degeneration in most of the major forebrain areas, e.g. cerebral cortex, thalamus, hypothalamus and basal ganglia. At the lower dose-rate, nerve terminal degeneration in the forebrain developed early (day 7) but exhibited a relatively limited spatial distribution, i.e. anteroventral thalamic nucleus and the pars reticulata of the substantia nigra. Several hippocampal regions were affected at a later time point (day 28), i.e. CA1 field and subicular complex. At both dose-rates, argyrophilic changes in forebrain nerve terminals developed prior to the onset of significant gait abnormalities. Thus, in forebrain, ACR intoxication produced a pure terminalopathy that developed prior to the onset of significant neurological changes and progressed as a function of exposure. Neither dose-rate used in this study was associated with axon degeneration in any forebrain region. Our findings indicate that nerve terminals were selectively affected in forebrain areas and, therefore, might be primary sites of ACR action.

Section snippets

INTRODUCTION

Acrylamide (ACR) is a well-recognized neurotoxicant that is used extensively in several chemical industries (US Environmental Protection Agency, 1985, US Environmental Protection Agency, 1988; Spencer and Schaumburg, 1974a, Spencer and Schaumburg, 1974b; Tilson, 1981). Exposure of humans and laboratory animals to monomeric ACR causes ataxia and hindlimb skeletal muscle weakness presumably mediated by axon damage classified as a central-peripheral distal axonopathy (see reviews by Gold and

Treatment and Neurological Evaluation of Animals

All aspects of this study were in accordance with the NIH Guide for Care and Use of Laboratory Animals and were approved by the Montefiore Medical Center Animal Care Committee. Adult male rats (Sprague–Dawley, 250–275 g; Taconic Farms, Germantown, NY) were used in this study. Rats were housed individually in polycarbonate boxes, and drinking water and Purina Rodent Laboratory Chow (Purina Mills Inc., St. Louis, MO) were available ad libitum. The animal room was maintained at approximately 22 °C

Neurological Evaluation

Rats intoxicated at the 50 mg/kg per day dose-rate exposure group had a mean (±S.E.M.) starting body weight of 267±3 g, which declined steadily to 250±5 g at endpoint (11 days; Fig. 1A). This represents a 6% decrease relative to initial weight. Rats in the age-matched control group had a similar starting body weight (270±4 g) and, during the 11 day experimental period, gained approximately 27% of original body weight (333±7 g). Thus, when compared to age-matched controls, the mean body weight of

DISCUSSION

We have suggested that axon degeneration was a secondary effect related to duration of ACR exposure (see reviews by LoPachin et al., 2000, LoPachin et al., 2002a). However, supporting evidence was primarily derived from studies in PNS tissues (e.g. sciatic, tibial and sural nerve; Lehning et al., 1998). Based on results from previous investigations (O’Shaughnessy and Losos, 1986, Burek et al., 1980, Yoshimura et al., 1992), the possibility existed that at higher dose-rates axonopathy was

SUMMARY

The present study has shown that, regardless of dose-rate, nerve terminal degeneration in rat forebrain was an early consequence of ACR intoxication. This effect was selective since neither dendrites, cell bodies nor axons exhibited argyrophilic changes at any dose-rate. In PNS, brainstem and spinal cord, ACR intoxication at the 50 mg/kg per day dose-rate also produced selective terminalopathy, whereas at the 21 mg/kg per day dose-rate, initial nerve terminal argyrophilia was followed by axon

Acknowledgements

Research presented in this manuscript was supported by a grant (to R.M.L.) from the National Institute of Environmental Health Sciences (RO1 ES03830-16) and by funds provided by the Procter and Gamble Co., Cincinnati, OH.

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