Early biochemical detection of delayed neurotoxicity resulting from developmental exposure to chloropyrifos

Developing animals are more sensitive than adults to the delayed neurotoxicity caused by chlorpyrifos exposure. In developing rat brain, chlorpyrifos doses that cause no discernible systemic toxicity and only a minor degree of cholinesterase inhibition, nevertheless evoke alterations in cell function and number that appear after several days' delay. In the current study, neonatal rats were exposed to subtoxic doses of chlorpyrifos (no weight loss or mortality) on either postnatal days 1-4, or postnatal days 11-14, and the effects on cellular RNA levels were determined in two brain regions that are targeted for delayed neurotoxicity-the brainstem and forebrain. In both regions, chlorpyrifos exposure evoked significant alterations in RNA concentration and content, variables that are ordinarily very tightly controlled in the developing brain. The effects on RNA appeared well before the deficits in cell function and number and showed a regional selectivity similar to that of subsequent, delayed neurotoxicity. Deficits in RNA were more prominent in the brainstem, an early-developing brain region, than in the forebrain, which develops later. These results suggest that chlorpyrifos can elicit delayed developmental neurotoxicity by targeting the pivotal macromolecules that control cell differentiation in a critical postmitotic period. The lower threshold for these cellular effects compared to that for systemic toxicity indicates that the developing brain is a selective target for chlorpyrifos, effects that should be considered in assessing safety thresholds.