Vol. 305, Issue 1, 375-384, April 2003

Repeated Exposures to Subthreshold Doses of Chlorpyrifos in Rats: Hippocampal Damage, Impaired Axonal Transport, and Deficits in Spatial Learning

A. V. Terry, Jr. , J. D. Stone, J. J. Buccafusco , D. W. Sickles, A. Sood and M. A. Prendergast

Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy (Augusta Campus) (A.V.T.), Alzheimer's Research Center and Department of Pharmacology and Toxicology (A.V.T., J.J.B., A.S.), and Department of Cell Biology and Anatomy (J.D.S., D.W.S.), Medical College of Georgia, Augusta, Georgia; Department of Veterans Affairs Medical Center (A.V.T., J.J.B.), Augusta, Georgia; and Department of Psychology (M.A.P.), University of Kentucky, Lexington, Kentucky

Organophosphorus (OP) compounds are detectable in the environment for years after use and endanger many populations. Although the effects of acutely toxic doses of many OP compounds are well described, much less is known about repeated low-level exposures. The purpose of these studies was to further evaluate potential toxicological effects of the extensively used OP pesticide chlorpyrifos (CPF) in rats. CPF, across a range of subthreshold doses (i.e., for acute toxicity), reduced rearing and sniffing activity and the magnitude of weight gain over 14 days of repeated exposure. Performance in a spatial learning task was impaired after 14 days of exposure to CPF (18.0 and 25.0 mg/kg) when testing was initiated 24 h after the last injection but not after a 14-day washout. However, inhibition of both fast anterograde and retrograde axonal transport was observed for up to 20 days after exposure to 25.0 mg/kg CPF. Studies using hippocampal cultures indicated that 8 days of continuous exposure to the parent compound, CPF (100 µM), resulted in cell toxicity and death. Furthermore, a dose (2.5 mg/kg) of CPF that had no effects on weight gain or memory performance when administered 5 days per week over 38 days impaired forelimb grip strength in the later days of testing. Collectively, these results indicate that repeated exposures to subthreshold doses of CPF may lead to growth retardation, behavioral abnormalities, and muscle weakness. Some of these symptoms may be attributed to effects of the OP on axonal transport.