Chlorpyrifos

Chlorpyrifos (CPY), an organophosphorus pesticide, is a neurotoxicant that acts through acetylcholinesterase inhibition, preventing the breakdown of acetylcholine, prolonging the actions of acetylcholine in the synapse (Aldridge 1990; Ray 1991). CPY was commonly used in the United States until it was discovered that the developing animal was especially sensitive to CPY toxicity. As outlined below, the effects of chlorpyrifos on the developing brain have been shown to be mediated by both excessive cholinergic stimulation and by noncholinergic mechanisms (Whitney et al. 1995). For instance, direct cholinergic effects were seen when a single dose of chlorpyrifos administered to neonatal rats immediately induced a reduction in DNA synthesis, which was also seen with the cholinergic agonist, nicotine. At the end of the first postnatal week after this single exposure, brain cholinergic regional selectivity was observed that could be blocked with antagonists. Immediate effects, however (see below), showed no selectivity. More prolonged neonatal exposures (1mg/kg/day) over two separate time frames, PN 1 to 4 vs. PN 11 to 14, however, did elicit decreases (long-term) in cholinergic innervation and tone, similar to the effects produced by nicotine. The earlier exposure resulted in the most profound effects, which were greatest in the hippocampus. Again, these effects are similar to the effects seen with nicotine after either a gestational or adolescent exposure. This may indicate that CPY may preferentially affect the programming of cell development, axongenesis, or synaptogenesis for the neurons providing the input to the hippocampus; since the hippocampus develops later than the other regions, there is more opportunity for the wiring of this region after a neonatal exposure.

However, during the immediate postexposure period when a single dose of CPY was administered, unlike with nicotine, there was no brain region selectivity; even regions with low cholinergic stimulation were affected. Other studies demonstrating noncholinergic effects of CPY exposure include a neonatal CPY exposure that reduced cholinesterase activity by only 20%, but still caused neurotoxicity (Song et al. 1997). It has been postulated that the noncholinergic effects of CPY appear to involve effects on cell signaling intermediates common to multiple neuronal and hormonal inputs, especially the adenylyl cyclase transduction pathway and transcription factors involved in promoting proliferation and differentiation (Song et al. 1997; Crumpton et al. 2000). Therefore, CPY affects brain development by at least two mechanisms, an early noncholinergic effect on second messenger systems and a later cholinergic effect.

Immune deficits have been observed after developmental CPY exposure during the same neonatal period that caused nervous system anomalies (Navarro et al. 2001b). A delayed expression of immune deficits was seen after a PN 1 to PN 4 exposure period. Exposure of neonatal rats to 1mg/kg/day during this period had no immediate effects (PN 5) on T cell mitogenic responses. However, once the animals reached adulthood, T cell responses were significantly impaired. This same delayed appearance of the effect of CPY was seen in the brain and was determined to be a direct cholinergic effect. A higher dose of CPY exposure (5 mg/kg/day) produced similar effects on the mitogenic response in adults. Only the mitogenic response was impaired, not the basal rate of proliferation or cell viability. In addition, the mitogenic response was impaired at a maximally effective concentration, indicating that the intrinsic ability of T cells to respond was impaired and not merely that the dose response curve had shifted. In summary, these results indicate that developmental exposure to CPY, known to produce lasting changes in neural function, elicits corresponding, long-term deficits in immune competence.

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