Chlorpyrifos interferes with cell development in rat brain regions

Chlorpyrifos, one of the most widely used pesticides, exhibits greater toxicity during development than in adulthood. We administered chlorpyrifos to neonatal rats in doses spanning the threshold for systemic toxicity and examined developing brain regions (brainstem, forebrain, cerebellum) for signs of interference with cell development using markers for cell packing density and cell number (DNA concentration and content) and cell size (protein/DNA ratio). Neonatal rats given 5 mg/kg of chlorpyrifos on postnatal days 1-4 showed significant mortality and the survivors exhibited severe cell loss in the brainstem; brainstem growth was maintained by enlargement of the remaining cells. This effect was not seen at 1 mg/kg, a dose that did not compromise survival or growth, nor was there any adverse effect at either dose in the forebrain, despite the fact that both brainstem and forebrain possess comparable cholinergic projections. When chlorpyrifos was administered later, on days 11-14, the major target for cell loss shifted from the brainstem to the forebrain and in this case, effects were seen at doses that did not compromise survival or growth. The loss of forebrain cell number occurred between 15 and 20 days of age rather than during the chlorpyrifos treatment. The cerebellum differed from the other regions in that it showed short-term elevations of DNA after chlorpyrifos exposure in either early or late postnatal periods; nevertheless, values then regressed to subnormal in parallel with the loss of cells in other regions. Thus, chlorpyrifos likely causes delayed cell death. Although regions rich in cholinergic projections, such as brainstem and forebrain, may be more affected than noncholinergic regions (cerebellum), the maturational timetable of each region (brainstem earliest, forebrain intermediate, cerebellum last) appears to be more important in setting the window of vulnerability. These results indicate that, even when growth or survival are unaffected, chlorpyrifos produces cellular deficits in the developing brain that could contribute to behavioral abnormalities.