Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats

Abstract

Chlorpyrifos (CPF) is a widely used insecticides which has been shown to alter brain cell development. The current project was conducted to determine whether there are persistent behavioral effects of early [1 mg/kg/day postnatal days (PNDs) 1–4] or late (5 mg/kg/day PNDs 11–14) postnatal CPF exposure in rats. We tested spontaneous alternation in a T-maze, locomotor activity in the Figure-8 apparatus and learning in the 16-arm radial maze, throughout adolescence and into adulthood. Exposure during either neonatal period elicited significant long-term effects on cognitive behavior. In the radial-arm maze, as has been seen previously, control male performed more accurately than control females. Early postnatal CPF exposure reversed this effect. With exposure on PNDs 1–4, females in the CPF group showed a reduction in working and reference memory errors in the radial maze, reducing their error rate to that seen in control males; in contrast, CPF-exposed males exhibited an increase in errors during the initial stages of training. When animals were exposed on PNDs 11–14 and then tested in adolescence and adulthood, males showed a significant slowing of response latency in the T-maze and the rate of habituation in the Figure-8 apparatus was slowed in both sexes. When females were challenged acutely with the muscarinic antagonist, scopolamine, they did not show reference memory impairment, whereas controls did; these results suggest that adaptations occur after CPF exposure that lead to loss of muscarinic cholinergic control of reference memory. No such changes were seen with a nicotinic cholinergic antagonist (mecamylamine). These results indicate that early neonatal exposure to CPF induces long-term changes in cognitive performance that, in keeping with the neurochemical changes seen previously, are distinctly gender-selective. Additional defects may be revealed by similar strategies that subject the animals to acute challenges, thus uncovering the adaptive mechanisms that maintain basal performance.

Introduction

Despite recent restrictions on its use in the home, chlorpyrifos (CPF) remains one of the most widely used insecticides in the world. The exposure of pregnant women and children to CPF represents a critical concern for this compound, in light of its identification as a neuroteratogen [1], [11], [16], [20]. In animal models, CPF treatment during brain cell acquisition and axonogenesis leads to neuronal loss and consequent abnormalities of synaptogenesis and synaptic activity [6], [9], [20]. The adverse effects on cholinergic neurotransmission [6], [20] are a particular concern, since cholinergic pathways are critically important for cognitive function [2]. Short-term behavioral studies indicate alterations in several activity measures after neonatal CPF treatment in rats [8], and additional effects on activity may emerge well after the end of administration [4]. Nevertheless, no systematic examination has been undertaken to characterize persistent cognitive defects after developmental CPF exposure.

The current studies focus on persistent changes in cognitive function involving hippocampal cholinergic circuitry. We have already found that neonatal CPF exposure in rats produces lasting reductions in hippocampal cholinergic presynaptic activity [21], an effect that displays a specific postnatal critical period and gender selectivity. Accordingly, the present behavioral studies were designed similarly: critical periods were examined by comparing early and late postnatal exposures, and effects were contrasted in males and females. Finally, to establish a connection between changes in cholinergic neurochemistry and behavioral alterations, we evaluated the behavioral response to challenges with muscarinic and nicotinic cholinergic receptor antagonists.