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Ameliorating the developmental neurotoxicity of chlorpyrifos: a mechanisms-based approach in PC12 cells
Theodore A Slotkin1, Emiko A MacKillop, Ian T Ryde
1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. t.slotkin@duke.edu
Background:
Organophosphate developmental neurotoxicity involves multiple mechanisms converging on neural cell replication and differentiation.
Objectives:
We evaluated mechanisms contributing to the adverse effects of chlorpyrifos (CPF) on DNA synthesis, cell number and size, and cell signaling mediated by adenylyl cyclase (AC) in PC12 cells, a neuronotypic cell line that recapitulates the essential features of developing mammalian neurons.
Results:
In undifferentiated cells, cholinergic receptor antagonists had little or no protective effect against the antimitotic actions of CPF; however, when nerve growth factor was used to evoke differentiation, the antagonists showed partial protection against deficits in cell loss and alteration in cell size elicited by CPF, but were ineffective in preventing the deterioration of AC signaling. Nicotine, which stimulates nicotinic acetylcholine receptors but also possesses a mixture of prooxidant/antioxidant activity, had adverse effects by itself but also protected undifferentiated cells from the actions of CPF and had mixed additive/protective effects on cell number in differentiating cells. The antioxidant vitamin E also protected both undifferentiated and differentiating cells from many of the adverse effects of CPF but worsened the impact on AC signaling. Theophylline, which prevents the breakdown of cyclic AMP, was the only agent that restored AC signaling to normal or supranormal levels but did so at further cost to cell replication.
Conclusions:
Our results show definitive contributions of cholinergic hyperstimulation, oxidative stress, and interference with AC signaling in the developmental neurotoxicity of CPF and point to the potential use of this information to design treatments to ameliorate these adverse effects.
Insights
Organophosphate pesticides like chlorpyrifos (CPF) harm developing neurons by disrupting cell replication and signaling. Treatments targeting cholinergic pathways, oxidative stress, and adenylyl cyclase (AC) may mitigate these neurotoxic effects.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Organophosphate (OP) compounds are known neurotoxicants.
- Developmental neurotoxicity (DNT) involves complex mechanisms affecting neural cell development.
- Chlorpyrifos (CPF) is a widely used organophosphate insecticide.
Purpose of the Study:
- To investigate the mechanisms underlying chlorpyrifos (CPF) neurotoxicity.
- To evaluate CPF's effects on DNA synthesis, cell number/size, and adenylyl cyclase (AC) signaling in PC12 cells.
- To explore potential protective agents against CPF-induced neurotoxicity.
Main Methods:
- Utilized PC12 cells, a neuronotypic cell line, to model mammalian neuronal development.
- Assessed the impact of CPF on cell replication, size, and AC signaling.
- Examined the effects of cholinergic receptor antagonists, nicotine, vitamin E, and theophylline on CPF-induced toxicity.
Main Results:
- Cholinergic antagonists offered partial protection against CPF's effects on cell loss and size during differentiation but not AC signaling.
- Nicotine and vitamin E demonstrated protective effects against some CPF-induced cellular damage, with mixed impacts on AC signaling.
- Theophylline normalized AC signaling but exacerbated CPF's effects on cell replication.
Conclusions:
- Developmental neurotoxicity of CPF involves cholinergic hyperstimulation, oxidative stress, and impaired AC signaling.
- These findings suggest potential therapeutic targets for mitigating CPF's adverse neurodevelopmental effects.
- Further research can guide the design of interventions against OP-induced neurotoxicity.
