Developmental Neurotoxicity of Low-Dose Diazinon Exposure of Neonatal Rats: Effects on Serotonin Systems in Adolescence and Adulthood

摘要

The developmental neurotoxicity of organophosphate pesticides targets serotonin (5HT) systems, which are involved in emotional and appetitive behaviors. We exposed neonatal rats to daily doses of diazinon on postnatal days 1–4, using doses (0.5 or 2 mg/kg) spanning the threshold for barely-detectable cholinesterase inhibition. We then evaluated the effects on 5HT1A and 5HT2 receptors, and on the 5HT transporter in cerebral cortical regions and the brainstem in adolescence through adulthood. Diazinon evoked a lasting deficit in 5HT1A receptors in males only, whereas it caused a small but significant increase in 5HT transporters in females; neither effect showed a significant regional selectivity. This pattern differed substantially from that seen in earlier work with another organophosphate, chlorpyrifos, which at pharmacodynamically similar doses spanning the threshold for cholinesterase inhibition, evoked a much more substantial, global upregulation of 5HT receptor expression; with chlorpyrifos, effects on receptors were seen in females, albeit to a lesser extent than in males, and were also regionally distinct. The effects of diazinon were nonmonotonic, showing larger alterations at the lower dose, likely reflecting positive trophic effects of cholinergic stimulation once the threshold for cholinesterase inhibition is exceeded. Our results reinforce the idea that different organophosphates have fundamentally distinct effects on the developmental trajectories of specific neurotransmitter systems, unrelated to their shared action as cholinesterase inhibitors. The effects on 5HT circuits expands the scope of behavioral endpoints that need to be considered in evaluating the developmental neurotoxicity of organophosphates.