Diazinon and parathion diverge in their effects on development of noradrenergic systems

Abstract

Organophosphate pesticides elicit developmental neurotoxicity through mechanisms over and above their shared property as cholinesterase inhibitors. We compared the consequences of neonatal exposure (postnatal days PN1-4) to diazinon or parathion on development of norepinephrine systems in rat brain, using treatments designed to produce equivalent effects on cholinesterase, straddling the threshold for barely-detectable inhibition. Norepinephrine levels were measured throughout development from the immediate posttreatment period (PN5), to early adolescence (PN30), young adulthood (PN60) and full adulthood (PN100); we assessed multiple brain regions containing all the major noradrenergic synaptic projections. Diazinon elicited a significant overall deficit of norepinephrine, whereas parathion produced a net increase. The effects were not immediately apparent (PN5) but rather emerged over the course of development, indicating that the organophosphate effects represent alteration of the trajectory of development, not just continuance of an initial injury. There were no comparable effects on β-adrenergic receptors, indicating that the presynaptic changes were not an adaptation to an underlying, primary effect on postsynaptic receptor signaling. Because we used the cholinesterase inhibition benchmark, the absolute dose of diazinon was much higher than that of parathion, since the latter is a more potent cholinesterase inhibitor. Our results are consistent with the growing evidence that the various organophosphates can differ in their impact on brain development and that consequently, the cholinesterase benchmark is an inadequate predictor of adverse neurodevelopmental effects.

Keywords: Brain development; Diazinon; Norepinephrine; Organophosphate pesticides; Parathion; β-Adrenergic receptor.

Figure 1

Effects of PN1-4 exposure to diazinon (DZN, 0.5 or 2 mg/kg) on norepinephrine levels. Data represent mean ± SE obtained from 6–12 animals of each sex at each age for each treatment group. Values are shown as percent change from control (see Table 1). Results of multivariate ANOVA appear at the top of the panel; lower-order tests for males and females or for individual ages or regions were not carried out because of the absence of a treatment interaction with these factors. Abbreviations: f/p frontal/parietal cortex, t/o temporal/occipital cortex, hp hippocampus, mb midbrain, bs brainstem, cb cerebellum, str striatum.

Figure 2

Effects of PN1-4 exposure to parathion (PRT, 0.1 or 0.2 mg/kg) on norepinephrine levels. Data represent mean ± SE obtained from 6–12 animals of each sex at each age for each treatment group. Values are shown as percent change from control (see Table 1). Results of multivariate ANOVA appear at the top of the panel; lower-order tests for males and females are shown within the panels as justified by the treatment × sex interaction. Treatment × [Age, Region] interactions were no longer detectable after separation by sex. Abbreviations: fb forebrain, mb+bs midbrain+brainstem, f/p frontal/parietal cortex, t/o temporal/occipital cortex, hp hippocampus, mb midbrain, bs brainstem, cb cerebellum.

Figure 3

Main effects of diazinon and parathion, collapsed across sex, region and dose. Data are the mean values of the changes across all bars for each age point in Figures 1 and 2.

Figure 4

Effects of PN1-4 exposure to diazinon (DZN, 0.5 or 2 mg/kg) or parathion (PRT, 0.1 or 0.2 mg/kg) on βAR binding. Data represent mean ± SE obtained from 6 animals of each sex for each treatment group. Values are shown as percent change from control (see Table 1). Results of multivariate ANOVA appear at the top of the panel; lower-order tests were not carried out because there was no significant treatment effect or treatment interaction with sex or region. Abbreviations: f/p frontal/parietal cortex, t/o temporal/occipital cortex, NS not significant.