Developmental neurotoxicity of parathion: progressive effects on serotonergic systems in adolescence and adulthood.
Neonatal exposures to organophosphates that are not acutely symptomatic or that produce little or no cholinesterase inhibition can nevertheless compromise the development and later function of critical neural pathways, including serotonin (5HT) systems that regulate emotional behaviors. We administered parathion to newborn rats on postnatal days (PN) 1-4 at doses spanning the threshold for detectable cholinesterase inhibition (0.1 mg/kg/day) and the first signs of loss of viability (0.2 mg/kg/day). In adolescence (PN30), young adulthood (PN60) and full adulthood (PN100), we measured radioligand binding to 5HT(1A) and 5HT(2) receptors, and to the 5HT transporter in the brain regions comprising all the major 5HT projections and 5HT cell bodies. Parathion caused a biphasic effect over later development with initial, widespread upregulation of 5HT(1A) receptors that peaked in the frontal/parietal cortex by PN60, followed by a diminution of that effect in most regions and emergence of deficits at PN100. There were smaller, but statistically significant changes in 5HT(2) receptors and the 5HT transporter. These findings stand in strong contrast to previous results with neonatal exposure to a different organophosphate, chlorpyrifos, which evoked parallel upregulation of all three 5HT synaptic proteins that persisted from adolescence through full adulthood and that targeted males much more than females. Our results support the view that the various organophosphates have disparate effects on 5HT systems, distinct from their shared property as cholinesterase inhibitors, and the targeting of 5HT function points toward the importance of studying the impact of these agents on 5HT-linked behaviors.
Slotkin
Theodore A
TA
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA. t.slotkin@duke.edu
Levin
Edward D
ED
Seidler
Frederic J
FJ
D000375:Aging / Q000502:physiology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003627:Data Interpretation, Statistical; D005260:Female; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D020258:Neurotoxicity Syndromes / Q000523:psychology*; D009929:Organ Size / Q000187:drug effects; D010278:Parathion / Q000633:toxicity*; D011247:Pregnancy; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000502:physiology; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D012727:Sex Characteristics
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D044348:Receptors, Serotonin, 5-HT2; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D010278:Parathion
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