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Developmental cholinotoxicants: nicotine and chlorpyrifos
1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slokin@duke.edu
Abstract:
The stimulation of cholinergic receptors in target cells during a critical developmental period provides signals that influence cell replication and differentiation. Accordingly, environmental agents that promote cholinergic activity evoke neurodevelopmental damage because of the inappropriate timing or intensity of stimulation. Nicotine evokes mitotic arrest in brain cells possessing high concentrations of nicotinic cholinergic receptors. In addition, the cholinergic overstimulation programs the expression of genes that evoke apoptosis and delayed cell loss. Effects of cholinesterase inhibitors exhibit many similarities to those of nicotine. Chlorpyrifos administered to developing rats in doses that do not evoke signs of overt toxicity decreased DNA synthesis and caused shortfalls in cell numbers in brain regions enriched in cholinergic innervation. In embryo cultures, chlorpyrifos also evoked apoptosis during neurulation. However, chlorpyrifos also evokes noncholinergic disruption of cell development by interfering with cell signaling via adenylyl cyclase, leading to widespread disruption that is not limited to cholinergic systems. We have tested this hypothesis in vitro with PC12 cells, which lack the enzymes necessary to produce chlorpyrifos oxon, the metabolite that inhibits cholinesterase. Chlorpyrifos inhibited DNA synthesis in undifferentiated PC12 cells, which have relatively few cholinergic receptors. Furthermore, chlorpyrifos was more effective than nicotine and its effects were not blocked by cholinergic antagonists. When cells were allowed to differentiate in the presence of chlorpyrifos, cell replication was inhibited even more profoundly and cell acquisition was arrested. At higher concentrations, chlorpyrifos also inhibited neuritic outgrowth. Thus, chlorpyrifos elicits damage by both noncholinergic and cholinergic mechanisms extending from early stages of neural cell replication through late stages of axonogenesis and terminal differentiation. Accordingly, the window of developmental vulnerability to chlorpyrifos is likely to extend from the embryonic period into postnatal life.
Insights
Environmental toxins like chlorpyrifos disrupt neurodevelopment through both cholinergic and non-cholinergic pathways, impacting cell replication and differentiation from embryonic stages into postnatal life.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Cholinergic receptor stimulation is crucial for normal neurodevelopment.
- Environmental agents can disrupt neurodevelopment by altering cholinergic activity.
- Nicotine and cholinesterase inhibitors cause neurodevelopmental damage via cholinergic pathways.
Purpose of the Study:
- To investigate the mechanisms of chlorpyrifos-induced neurodevelopmental damage.
- To determine if chlorpyrifos exerts effects through both cholinergic and non-cholinergic pathways.
- To characterize the developmental window of vulnerability to chlorpyrifos.
Main Methods:
- Administered chlorpyrifos to developing rats and embryo cultures.
- Utilized in vitro studies with PC12 cells (lacking cholinesterase metabolite production).
- Assessed effects on DNA synthesis, cell numbers, apoptosis, and neuritic outgrowth.
Main Results:
- Chlorpyrifos decreased DNA synthesis and cell numbers in specific brain regions of rats.
- In embryo cultures, chlorpyrifos induced apoptosis during neurulation.
- In PC12 cells, chlorpyrifos inhibited DNA synthesis and cell replication via non-cholinergic mechanisms, independent of cholinergic antagonists.
Conclusions:
- Chlorpyrifos causes neurodevelopmental damage through both non-cholinergic and cholinergic mechanisms.
- Effects span from early cell replication to later stages of differentiation and axonogenesis.
- Vulnerability to chlorpyrifos extends from embryonic to postnatal development.