Behavioral alterations in adolescent and adult rats caused by a brief subtoxic exposure to chlorpyrifos during neurulation.
The widely used organophosphate insecticide, chlorpyrifos (CPF), elicits neurobehavioral abnormalities after apparently subtoxic neonatal exposures. In the current study, we administered 1 or 5 mg/kg/day of CPF to pregnant rats on gestational days 9-12, the embryonic phase spanning formation and closure of the neural tube. Although there were no effects on growth or viability, offspring showed behavioral abnormalities when tested in adolescence and adulthood. In the CPF-exposed groups, locomotor hyperactivity was noted in early T-maze trials, and in the elevated plus-maze; alterations in the rate of habituation were also identified. Learning and memory were adversely affected, as assessed using the 16-arm radial maze. Although all CPF-exposed animals eventually learned the task, reference and working memory were impaired in the early training sessions. After training, rats in the CPF group did not show the characteristic amnestic effect of scopolamine, a muscarinic acetylcholine antagonist, suggesting that, unlike the situation in the control group, muscarinic pathways were not used to solve the maze. These results indicate that apparently subtoxic CPF exposure during neurulation adversely affects brain development, leading to behavioral anomalies that selectively include impairment of cholinergic circuits used in learning and memory. The resemblance of these findings to those of late gestational or neonatal CPF exposure indicates a prolonged window of vulnerability of brain development to CPF.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Laura M
LM
Icenogle
N Channelle
NC
Christopher
W Paul
WP
Blackwelder
D Patrick
DP
Caldwell
Dan
D
Qiao
Frederic J
FJ
Seidler
Theodore A
TA
Slotkin
Edward D
ED
Levin
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D001526:Behavioral Symptoms / Q000139:chemically induced*; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000254:growth & development / Q000503:physiopathology; D004390:Chlorpyrifos / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D007266:Inhibition, Psychological; D007306:Insecticides / Q000633:toxicity*; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology
D007306:Insecticides; D018727:Muscarinic Antagonists; D012601:Scopolamine; D004390:Chlorpyrifos