title: Early postnatal parathion exposure in rats causes sex-selective cognitive impairment and neurotransmitter defects which emerge in aging.
abstract: Developmental exposure of rats to the organophosphate (OP) pesticides leads to altered neurobehavioral function in juvenile and young adult stages. The current study was conducted to determine whether effects of neonatal parathion exposure on cognitive performance persist in older adult and aged rats, and the relationship of behavioral changes to underlying cholinergic and serotonergic mechanisms. We administered parathion to rat pups on postnatal days 1-4, at doses spanning the threshold for the initial signs of systemic toxicity and for barely detectable cholinesterase inhibition (0.1 or 0.2 mg/kg/day). Beginning at 14 months of age and continuing until 19 months, the rats were trained in the 16-arm radial maze. Controls showed the normal sex difference in this spatial learning and memory task, with the males committing significantly fewer working memory errors than females. Neonatal parathion exposure eliminated the sex difference primarily by causing impairment in males. In association with the effects on cognitive performance, neonatal parathion exposure elicited widespread abnormalities in indices of serotonergic (5HT) and cholinergic synaptic function, characterized by upregulation of 5HT(2) receptors and the 5HT transporter, deficits in choline acetyltransferase activity and nicotinic cholinergic receptors, and increases in hemicholinium-3 binding to the presynaptic choline transporter. Within-animal correlations between behavior and neurochemistry indicated a specific correlation between working memory performance and hippocampal hemicholinium-3 binding; parathion exposure eliminated this relationship. Like the behavioral effects, males showed greater effects of parathion on neurochemical parameters. This study demonstrates the sex-selective, long-term behavioral alterations caused by otherwise nontoxic neonatal exposure to parathion, with effects increasingly expressed with aging.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. edlevin@duke.edu
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.forename: Olga A
authors.initials: OA
authors.lastname: Timofeeva
authors.forename: Liwei
authors.initials: L
authors.lastname: Yang
authors.forename: Ann
authors.initials: A
authors.lastname: Petro
authors.forename: Ian T
authors.initials: IT
authors.lastname: Ryde
authors.forename: Nicola
authors.initials: N
authors.lastname: Wrench
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: Seidler
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Slotkin
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006426:Hemicholinium 3 / Q000494:pharmacology; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D010278:Parathion / Q000633:toxicity*; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012743:Sex Preselection / Q000523:psychology*
chemical_list: D007306:Insecticides; D014179:Neurotransmitter Uptake Inhibitors; D011978:Receptors, Nicotinic; D006426:Hemicholinium 3; D012701:Serotonin; D010278:Parathion; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine