Contemporary Issues In Toxicology
Rate of Neurotoxicant Exposure Determines Morphologic Manifestations of Distal Axonopathy

https://doi.org/10.1006/taap.2000.8984Get rights and content

Abstract

Exposure to a variety of agricultural, industrial, and pharmaceutical chemicals produces nerve damage classified as a central–peripheral distal axonopathy. Morphologically, this axonopathy is characterized by distal axon swellings and secondary degeneration. Over the past 25 years substantial research efforts have been devoted toward deciphering the molecular mechanisms of these presumed hallmark neuropathic features. However, recent studies suggest that axon swelling and degeneration are related to subchronic low-dose neurotoxicant exposure rates (i.e., mg toxicant/kg/day) and not to the development of neurophysiological deficits or behavioral toxicity. This suggests these phenomena are nonspecific and of uncertain pathophysiologic relevance. This possibility has significant implications for research investigating mechanisms of neurotoxicity, development of exposure biomarkers, design of risk assessment models, neurotoxicant classification schemes, and clinical diagnosis and treatment of toxic neuropathies. In this commentary we will review the evidence for the dose-related dependency of distal axonopathies and discuss how this concept might influence our current understanding of chemical-induced neurotoxicities.

References (84)

  • R.M. LoPachin et al.

    Mechanism of calcium entry during axon injury and degeneration

    Toxicol. Appl. Pharmacol.

    (1997)
  • C.H. Martenson et al.

    In vitro acrylamide exposure alters growth cone morphology

    Toxicol. Appl. Pharmacol.

    (1995)
  • S. Monaco et al.

    Axonal transport of neurofilament is accelerated in peripheral nerve during 2,5-hexanedione intoxication

    Brain Res.

    (1989)
  • S. Ochs et al.

    The origin and nature of beading: A reversible transformation of the shape of nerve fibers

    Prog. Neurobiol.

    (1997)
  • C.K. Rosenberg et al.

    dl-versus meso-3,4-dimethyl-2,5-hexanedione: A morphometric study of the proximodistal distribution of axonal swellings in the anterior root of the rat

    Toxicol. Appl Pharmacol.

    (1987)
  • D.W. Sickles et al.

    Effects of neurofilamentous axonopathy-producing neurotoxicants on in vitro production of ATP by brain mitochondria

    Brain Res.

    (1990)
  • M.B. Abou-Donia et al.

    Neurotoxicity of glycidamide, an acrylamide metabolite, following intraperitoneal injections in rats

    J. Toxicol. Environ. Health

    (1993)
  • D.C. Anthony et al.

    The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. I. Accelerated clinical neuropathy is accompanied by more proximal axonal swellings

    Toxicol. Appl. Pharmacol.

    (1983)
  • D. Barber et al.

    Formation of acrylamide (ACR) and glycidamide (GLY) hemoglobin adducts in ACR-exposed rats

    Toxicologist

    (2000)
  • A.R. Berger et al.

    Human peripheral nerve disease (peripheral neuropathies)

  • M.A. Bisby et al.

    Acrylamide neuropathy: Changes in composition of proteins of fast axonal transport resemble those observed in regenerating axons

    J. Neurochem.

    (1987)
  • W.G. Bradley et al.

    Axoplasmic flow in axonal neuropathies. I. Axoplasmic flow in cats with toxic neuropathies

    Brain

    (1973)
  • D.J. Brat et al.

    Acrylamide and glycidamide impair neurite outgrowth in differentiation N1E.115 neuroblastoma without disturbing rapid bi-directional transport of organelles observed by video microscopy

    J. Neurochem.

    (1993)
  • M.J. Brown et al.

    Nerve conduction slowing precedes demyelination in experimental n-butyl ketone (MBK) neuropathy

  • J.D. Burek et al.

    Subchronic toxicity of acrylamide administered to rats in drinking water followed by up to 144 days of recovery

    J. Environ. Pathol. Toxicol.

    (1980)
  • J.B. Cavanagh

    The significance of the “dying-back” process in experimental and human neurological disease

    Int. Rev. Exp. Pathol.

    (1964)
  • J.B. Cavanagh et al.

    Ultrastructural features of the Purkinje cell damage caused by acrylamide in the rat: A new phenomenon in cellular neurophysiology

    J. Neurocytol.

    (1983)
  • F.C. Chiu et al.

    γ-Diketone peripheral neuropathy. II. Neurofilament subunit content

    Toxicol. Appl. Pharmacol.

    (2000)
  • D. Couri et al.

    Toxicity and the metabolism of the neurotoxic hexacarbons n-hexane, 2-hexanone and 2,5-hexanedione

    Annu. Rev. Pharmacol. Toxicol.

    (1982)
  • Environmental Protection Agency, 1988, Preliminary Assessment of Health Risks from Exposure to Acrylamide, Office of...
  • P.M.Barnes Fullerton et al.

    Peripheral neuropathy in rats produced by acrylamide

    Br. J. Ind. Med.

    (1966)
  • J.D. Glass et al.

    Neurofilament redistribution in transected nerves: Evidence for bi-directional transport of neurofilaments

    J. Neurosci.

    (1991)
  • B.G. Gold et al.

    Regulation of aberrant neurofilament phosphorylation in neuronal perikarya. II. Correlation with continued axonal elongation following axotomy

    J. Neuropathol. Exp. Neurol.

    (1991)
  • B.G Gold et al.

    Somatofugal axonal atrophy precedes development of axonal degeneration in acrylamide neuropathy

    Arch. Toxicol.

    (1992)
  • B.G. Gold et al.

    Neurotrophic function in normal nerves and in peripheral neuropathies

  • D.G. Graham et al.

    Pathogenetic studies of hexane and carbon disulfide neurotoxicity

    Crit. Rev. Toxicol.

    (1995)
  • Griffin, J. W.1992. Neurotoxicant-induced axonal degeneration. In Neurotoxicology (H. A. Tilson, and C. Mitchell,...
  • C.H. Harris et al.

    Toxic neurofilamentous axonopathies and fast axonal transport. V. Reduced bidirectional vesicle transport in cultured neurons by acrylamide and glycidamide

    J. Environ. Health Toxicol.

    (1994)
  • G.J. Harry

    Acrylamide-induced alterations in axonal transport

    Mol. Neurobiol.

    (1992)
  • H.B. Jones et al.

    The axon reaction in spinal ganglion neurons of acrylamide-treated rats

    Acta Neuropathol.

    (1986)
  • E.J. Lehning et al.

    Changes in Na-K ATPase and protein kinase C activities in peripheral nerve of acrylamide-treated rats

    J. Toxicol. Environ. Health

    (1994)
  • Cited by (37)

    • Relationship between Antioxidants and Acrylamide Formation

      2016, Acrylamide in Food: Analysis, Content and Potential Health Effects
    • Development of new indole-derived neuroprotective agents

      2011, Bioorganic and Medicinal Chemistry
      Citation Excerpt :

      The in vivo neuroprotective effect of TRP and the novel synthesized indole derivatives, 9b, 12c, 14a, and 17, against ACR-induced neurotoxicity in rats was investigated. ACR is a well established agent for induction of neurotoxicity.20,21 Neuronal damage due to ACR was detected by measuring: (1) the levels of brain monoamines, adrenaline (AD), noradrenalin (NA) and dopamine (DA), (2) the end product of brain lipid peroxidation, malondialdehyde, (MDA), (3) the activity of brain antioxidative enzymes, glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione content (GSH), and (4) the activity of brain enzymes lactate dehydrogenase (LDH) and creatine kinase (CK).

    View all citing articles on Scopus
    1

    To whom correspondence should be addressed at Montefiore Medical Center, Anesthesia Research–Moses 7, 111 E. 210th St., Bronx, NY 10467-2490. Fax: (718) 515-4903; E-mail: [email protected].

    View full text