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Developmental Neurotoxicity of Fipronil and Rotenone on a Human Neuronal In Vitro Test System.

Anne Schmitz1, Silke Dempewolf1, Saime Tan1

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Fipronil and its metabolite fipronil sulfone show specific developmental neurotoxicity in human neuronal precursor cells. This pesticide exposure impacts neuronal differentiation and migration, highlighting concerns for early development.

Keywords:
DNTDifferentiationMigrationNT2NTera-2Neurite outgrowth

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Area of Science:

  • Neuroscience
  • Toxicology
  • Developmental Biology

Background:

  • Pesticide exposure during development can cause neurological defects.
  • Fipronil's status as a developmental neurotoxicant is debated, with conflicting in vitro and in vivo study results.
  • Recent discovery of fipronil in chicken eggs has heightened public concern.

Purpose of the Study:

  • To investigate the in vitro developmental neurotoxicity of fipronil and its metabolite, fipronil sulfone.
  • To compare the effects of fipronil and fipronil sulfone with the known neurotoxicant rotenone on human neuronal precursor cells.
  • To elucidate the mechanisms underlying fipronil's potential neurotoxicity, including oxidative stress and cell migration pathways.

Main Methods:

  • Utilized the human neuronal precursor cell line NT2 for in vitro testing.
  • Assessed developmental neurotoxicity (DNT) endpoints: neurite outgrowth, neuronal differentiation, and precursor cell migration.
  • Administered fipronil, fipronil sulfone, and rotenone at varying concentrations.
  • Investigated the role of oxidative stress using n-acetyl cysteine and cell migration pathways using Y-27632.

Main Results:

  • Rotenone impaired all tested DNT endpoints in a dose-dependent manner at nanomolar concentrations.
  • Fipronil and fipronil sulfone (micromolar range) specifically inhibited cell migration and neuronal differentiation, but not neurite outgrowth.
  • Fipronil sulfone exhibited stronger inhibitory effects than fipronil.
  • N-acetyl cysteine ameliorated fipronil's effects, indicating oxidative stress involvement.
  • Y-27632 counteracted the migration inhibition caused by all three compounds.

Conclusions:

  • Fipronil and fipronil sulfone demonstrate specific in vitro developmental neurotoxicity in human model neurons.
  • The findings underscore the importance of evaluating pesticide metabolites alongside parent compounds.
  • Results suggest that fipronil's neurotoxic effects may involve oxidative stress and impact neuronal migration and differentiation.