title: 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.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: t.slotkin@duke.edu.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Skavicus
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D003976:Diazinon / Q000633:toxicity*; D005260:Female; D007306:Insecticides / Q000633:toxicity; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010278:Parathion / Q000633:toxicity*; D017207:Rats, Sprague-Dawley
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D010278:Parathion; D009638:Norepinephrine; D003976:Diazinon
keywords: Brain development; Diazinon; Norepinephrine; Organophosphate pesticides; Parathion; β-Adrenergic receptor