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Developmental neurotoxicants target neurodifferentiation into the serotonin phenotype: Chlorpyrifos, diazinon,

Theodore A Slotkin1, Frederic J Seidler

  • 1Department of Pharmacology and Cancer Biology Box 3813, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu

Toxicology and Applied Pharmacology
|October 7, 2008
PubMed

Insights

Developmental exposure to organophosphates (OPs) alters serotonin (5HT) pathways, with chlorpyrifos and diazinon affecting 5HT biosynthesis and receptors differently. These findings link early neurotoxicant exposure to long-term synaptic changes.

Area of Science:

  • Neuroscience
  • Toxicology
  • Developmental Biology

Background:

  • Developmental exposure to organophosphates (OPs) can cause lasting changes in serotonin (5HT) signaling and behavior.
  • Disparities exist in the effects of different OPs and other neurotoxicants on neural development.

Purpose of the Study:

  • To contrast the effects of chlorpyrifos and diazinon, along with non-OP neurotoxicants (dieldrin, Ni(2+)), on serotonin pathways in a neurodevelopmental model.
  • To investigate the direct mechanisms of developmental neurotoxicant action on specific transmitter pathways and their link to long-term synaptic function.

Main Methods:

  • Utilized undifferentiated and differentiating PC12 cells as a neurodevelopmental model.
  • Exposed cells to 30 microM of agents (chlorpyrifos, diazinon, dieldrin, Ni(2+)) for 24 or 72 hours, ensuring no cytotoxicity.
  • Evaluated mRNA expression for proteins involved in 5HT biosynthesis, storage, degradation, and 5HT receptors.

Main Results:

  • Both chlorpyrifos and diazinon induced tryptophan hydroxylase (rate-limiting enzyme for 5HT synthesis), with chlorpyrifos showing a greater effect.
  • Chlorpyrifos and diazinon suppressed 5HT transporter genes, potentially increasing extracellular 5HT.
  • Chlorpyrifos enhanced most 5HT receptor subtypes, while diazinon and dieldrin suppressed them. Ni(2+) had distinct effects, suppressing tryptophan hydroxylase and enhancing vesicular monoamine transporter.
  • Dieldrin showed stronger induction of tryptophan hydroxylase and similar receptor effects to diazinon, despite belonging to a different pesticide class.

Conclusions:

  • Findings provide initial evidence linking early neurotoxicant exposure mechanisms to long-term synaptic function and behavioral outcomes.
  • Supports the utility of in vitro test systems for elucidating mechanisms and consequences of diverse neurotoxicants.
  • Highlights differential impacts of various neurotoxicants, including OPs and heavy metals, on serotonin signaling pathways during development.

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