Chlorpyrifos-oxon disrupts zebrafish axonal growth and motor behavior

Dongren Yang, Holly Lauridsen, Kalmia Buels, Lai Har Chi, Jane La Du, Donald A. Bruun, James R. Olson, Robert L. Tanguay, Pamela J. Lein

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Axonal morphology is a critical determinant of neuronal connectivity, and perturbation of the rate or extent of axonal growth during development has been linked to neurobehavioral deficits in animal models and humans. We previously demonstrated that the organophosphorus pesticide (OP) chlorpyrifos (CPF) inhibits axonal growth in cultured neurons. In this study, we used a zebrafish model to determine whether CPF, its oxon metabolite (CPFO), or the excreted metabolite trichloro-2-pyridinol (TCPy) alter spatiotemporal patterns of axonal growth in vivo. Static waterborne exposure to CPFO, but not CPF or TCPy, at concentrations ≥ 0.03μM from 24-to 72-h post fertilization significantly inhibited acetylcholinesterase, and high-performance liquid chromatography detected significantly more TCPy in zebrafish exposed to 0.1μM CPFO versus 1.0μM CPF. These data suggest that zebrafish lack the metabolic enzymes to activate CPF during these early developmental stages. Consistent with this, CPFO, but not CPF, significantly inhibited axonal growth of sensory neurons, primary motoneurons, and secondary motoneurons at concentrations ≥ 0.1μM. Secondary motoneurons were the most sensitive to axonal growth inhibition by CPFO, which was observed at concentrations that did not cause mortality, gross developmental defects, or aberrant somatic muscle differentiation. CPFO effects on axonal growth correlated with adverse effects on touch-induced swimming behavior, suggesting the functional relevance of these structural changes. These data suggest that altered patterns of neuronal connectivity contribute to the developmental neurotoxicity of CPF and demonstrate the relevance of zebrafish as a model for studying OP developmental neurotoxicity.

Original languageEnglish (US)
Pages (from-to)146-159
Number of pages14
JournalToxicological Sciences
Volume121
Issue number1
DOIs
StatePublished - 2011
Externally publishedYes

Keywords

  • Axon outgrowth
  • Chlorpyrifos
  • Chlorpyrifos-oxon
  • Developmental neurotoxicology
  • Organophosphorus pesticides
  • Zebrafish

ASJC Scopus subject areas

  • Toxicology

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  • Cite this

    Yang, D., Lauridsen, H., Buels, K., Chi, L. H., La Du, J., Bruun, D. A., Olson, J. R., Tanguay, R. L., & Lein, P. J. (2011). Chlorpyrifos-oxon disrupts zebrafish axonal growth and motor behavior. Toxicological Sciences, 121(1), 146-159. https://doi.org/10.1093/toxsci/kfr028