Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations.
Use of chlorpyrifos (CPF) has been curtailed due to its developmental neurotoxicity. In rats, postnatal CPF administration produces lasting changes in cognitive performance, but less information is available about the effects of prenatal exposure. We administered CPF to pregnant rats on gestational days (GD) 17-20, a peak period of neurogenesis, using doses (1 or 5 mg/kg/day) below the threshold for fetal growth impairment. We then evaluated performance in the T-maze, Figure-8 apparatus and 16-arm radial maze, beginning in adolescence and continuing into adulthood. CPF elicited initial locomotor hyperactivity in the T-maze. Females showed slower habituation in the Fig. 8 maze; no effects were seen in males. In the radial-arm maze, females showed impaired choice accuracy for both working and reference memory and again, males were unaffected. Despite the deficits, all animals eventually learned the maze with continued training. At that point, we challenged them with the muscarinic antagonist, scopolamine, to determine the dependence of behavioral performance on cholinergic function. Whereas control females showed impairment with scopolamine, CPF-exposed females did not, implying that the delayed acquisition of the task had been accomplished through alternative mechanisms. The differences were specific to muscarinic circuits, as control and CPF groups responded similarly to the nicotinic antagonist, mecamylamine. Surprisingly, adverse effects of CPF were greater in the group receiving 1 mg/kg as compared to 5 mg/kg. Promotional effects of acetylcholine (ACh) on cell differentiation may thus help to offset CPF-induced developmental damage that occurs through other noncholinergic mechanisms. Our results indicate that late prenatal exposure to CPF induces long-term changes in cognitive performance that are distinctly gender-selective. Additional defects may be revealed by similar strategies that subject the animals to acute challenges, thus, uncovering the adaptive mechanisms that maintain basal performance.
Levin
Edward D
ED
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. edlevin@duke.edu
Addy
Nii
N
Baruah
Avanti
A
Elias
Alana
A
Christopher
N Channelle
NC
Seidler
Frederic J
FJ
Slotkin
Theodore A
TA
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004390:Chlorpyrifos / Q000633:toxicity*; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D001523:Mental Disorders / Q000139:chemically induced* / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D012601:Scopolamine / Q000494:pharmacology; D012727:Sex Characteristics
D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D012601:Scopolamine; D004390:Chlorpyrifos