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Studies on the Molecular Pathogenesis of Organophosphorus Compound-Induced Delayed Neurotoxicity (OPIDN)

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Insecticide Action

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Abstract

Tri-o-cresyl phosphate (TOCP) produces organophosphorus compound-induced delayed neurotoxicity (OPIDN) in humans and in sensitive animal species. After a delay period of 6 to 14 days, neurologic dysfunctions are manifested as ataxia and bilateral paralysis. Early lesions are aggregates of neurotubules and neurofilaments which later condense. Neurotoxic doses of TOCP resulted in an increased activity of Ca2+-calmodulin kinase II (CaM kinase II). This resulted in enhanced CaM kinase II-dependent autophosphorylation as well as phosphorylation of cytoskeletal proteins, i.e., α- and β-tubulin, MAP-2, and neurofilament triplet proteins that interfere with their assembly. Also, phosphorylation of MAP-2 reduces its interaction with tubulin and diminishes its ability to promote tubulin assembly into microtubules. Aggregation and accumulation of such structures disrupt axonal transport and lead to the accumulation of mitochondria and/or endoplasmic reticulum in the distal parts of the axons with subsequent release of Ca2+ into the axoplasm. This disrupts axonal membrane mechanisms for intracellular/extracellular ionic gradient, which results in focal internodal swelling and degeneration that spreads somatofugally to involve the entire distal axon.

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Authors and Affiliations

  1. Department of Pharmacology, Duke University Medical Center, Durham, North Carolina, USA

    Mohamed B. Abou-Donia & Daniel M. Lapadula

Authors
  1. Mohamed B. Abou-Donia
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  2. Daniel M. Lapadula
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Editors and Affiliations

  1. Northwestern University Medical School, Chicago, Illinois, USA

    Toshio Narahashi

  2. Mississippi State University, Mississippi State, Mississippi, USA

    Janice E. Chambers

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© 1989 Plenum Press, New York

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Abou-Donia, M.B., Lapadula, D.M. (1989). Studies on the Molecular Pathogenesis of Organophosphorus Compound-Induced Delayed Neurotoxicity (OPIDN). In: Narahashi, T., Chambers, J.E. (eds) Insecticide Action. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-1324-3_11

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  • DOI: https://doi.org/10.1007/978-1-4684-1324-3_11

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4684-1326-7

  • Online ISBN: 978-1-4684-1324-3

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