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.

Differences in neurotoxic outcomes of organophosphorus pesticides revealed via multi-dimensional screening in adult and regenerating planarians

“…OP-induced DNT in animals in the absence of significant AChE inhibition has been linked to a multitude of other secondary targets as well, depending on the system, OP, and exposure protocol (Dam et al, 2000;Slotkin, 2006;Slotkin et al, 2006b;Yang et al, 2008;Brown and Pearson, 2015;Mamczarz et al, 2016;Schmitt et al, 2019). Other proposed secondary targets include nicotinic AChRs, other esterases, and non-esterase, non-cholinergic targets such as serotonin receptors, cytoskeletal proteins, mitochondria, and glial cells (Pope, 1999;Guizzetti et al, 2005;Pope et al, 2005a;Slotkin et al, 2006bSlotkin et al, , 2017Carr et al, 2014;Burke et al, 2017). The impact of all of these effects remains unclear, however, because it has been difficult to ascertain direct connections between molecular/cellular endpoints and brain function (behavioral) deficits.…”

Differences in neurotoxic outcomes of organophosphorus pesticides revealed via multi-dimensional screening in adult and regenerating planarians

“…OP-induced DNT in animals in the absence of significant AChE inhibition has been linked to a multitude of other secondary targets as well, depending on the system, OP, and exposure protocol ( Dam et al, 2000 ; Slotkin et al, 2006b ; Slotkin, 2006 ; Yang et al, 2008 ; Brown and Pearson, 2015 ; Mamczarz et al, 2016 ; Schmitt et al, 2019 ). Other proposed secondary targets include nicotinic AChRs, other esterases, and non-esterase, non-cholinergic targets such as serotonin receptors, cytoskeletal proteins, mitochondria, and glial cells ( Pope, 1999 ; Guizzetti et al, 2005 ; Pope et al, 2005 ; Slotkin et al, 2006b ; Carr et al, 2014 ; Burke et al, 2017 ; Slotkin et al, 2017 ). The impact of all of these effects remains unclear, however, because it has been difficult to ascertain direct connections between molecular/cellular endpoints and brain function (behavioral) deficits.…”