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Rate of neurotoxicant exposure determines morphologic manifestations of distal axonopathy
R M LoPachin1, E J Lehning, L A Opanashuk
1Department of Anesthesiology, Albert Einstein College of Medicine/Montefiore Medical Center, 111 E. 210th Street, Bronx, New York, 10467-2490, USA. lopachin@aecom.yu.edu
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.
Insights
Chemicals can cause nerve damage called distal axonopathy. Recent research suggests that nerve swelling and degeneration may be nonspecific, questioning their relevance in neurotoxicity assessment.
Area of Science:
- Neuroscience
- Toxicology
- Pathology
Background:
- Chemical exposures (agricultural, industrial, pharmaceutical) can cause central-peripheral distal axonopathy.
- This nerve damage is morphologically characterized by distal axon swellings and secondary degeneration.
- Significant research has focused on the molecular mechanisms of these neuropathic features.
Purpose of the Study:
- To review evidence for dose-related dependency in distal axonopathies.
- To discuss the implications of this dose-dependency for understanding chemical-induced neurotoxicity.
Main Methods:
- Review of existing research on neurotoxicant exposure and distal axonopathies.
- Analysis of the relationship between exposure rates (mg/kg/day) and observed neuropathic features.
- Discussion of the pathophysiological relevance of axon swelling and degeneration.
Main Results:
- Recent studies indicate axon swelling and degeneration may correlate with subchronic low-dose exposure rates.
- These morphological changes might not be directly linked to neurophysiological deficits or behavioral toxicity.
- The relevance of these phenomena as specific indicators of neurotoxicity is questioned.
Conclusions:
- Distal axonopathies might be nonspecific phenomena, dependent on exposure rates rather than specific molecular mechanisms.
- This challenges current understanding of neurotoxicity mechanisms, biomarker development, and risk assessment models.
- Re-evaluation of toxic neuropathies' diagnosis and treatment may be necessary based on dose-dependency.