Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus pesticide chlorpyrifos: Toxicological implications.
Exposure of the developing brain to chlorpyrifos (CPF), an organophosphorus (OP) pesticide used extensively in agriculture worldwide, has been associated with increased prevalence of cognitive deficits in children, particularly boys. The present study was designed to test the hypothesis that cognitive deficits induced by prenatal exposure to sub-acute doses of CPF can be reproduced in precocial small species. To address this hypothesis, pregnant guinea pigs were injected daily with CPF (25mg/kg,s.c.) or vehicle (peanut oil) for 10days starting on presumed gestation day (GD) 53-55. Offspring were born around GD 65, weaned on postnatal day (PND) 20, and subjected to behavioral tests starting around PND 30. On the day of birth, butyrylcholinesterase (BuChE), an OP bioscavenger used as a biomarker of OP exposures, and acetylcholinesterase (AChE), a major molecular target of OP compounds, were significantly inhibited in the blood of CPF-exposed offspring. In their brains, BuChE, but not AChE, was significantly inhibited. Prenatal CPF exposure had no significant effect on locomotor activity or on locomotor habituation, a form of non-associative memory assessed in open fields. Spatial navigation in the Morris water maze (MWM) was found to be sexually dimorphic among guinea pigs, with males outperforming females. Prenatal CPF exposure impaired spatial learning more significantly among male than female guinea pigs and, consequently, reduced the sexual dimorphism of the task. The results presented here, which strongly support the test hypothesis, reveal that the guinea pig is a valuable animal model for preclinical assessment of the developmental neurotoxicity of OP pesticides. These findings are far reaching as they lay the groundwork for future studies aimed at identifying therapeutic interventions to treat and/or prevent the neurotoxic effects of CPF in the developing brain.
Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Jacek
J
Mamczarz
Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Joseph D
JD
Pescrille
Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Lisa
L
Gavrushenko
Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Richard D
RD
Burke
Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
William P
WP
Fawcett
Program of Comparative Medicine and Departments of Pathology and Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Louis J
LJ
DeTolla
Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Hegang
H
Chen
Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
Edna F R
EFR
Pereira
Division of Translational Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201, United States. Electronic address: ealbuquerque@som.umaryland.edu.
Edson X
EX
Albuquerque
D000367:Age Factors; D000818:Animals; D004390:Chlorpyrifos / Q000633:toxicity*; D002802:Cholinesterases / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D007306:Insecticides / Q000633:toxicity*; D007859:Learning Disabilities / Q000209:etiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000503:physiopathology; D065853:Spatial Learning / Q000187:drug effects*
D007306:Insecticides; D002802:Cholinesterases; D004390:Chlorpyrifos
Acetylcholinesterase; Butyrylcholinesterase; Guinea pig; Learning; Organophosphorus; Pesticide