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Cholinergic and noncholinergic brain biomarkers of insecticide exposure and effects

Murray State University, Breathitt Veterinary Center, Toxicology Department, P.O. Box 2000, 715 North Drive, Hopkinsville, Kentucky 42241-2000, USA

J T Goad

Murray State University, Breathitt Veterinary Center, Toxicology Department, Hopkinsville, Kentucky, USA

D Milatovic

W-D Dettbarn

Vanderbilt University, Medical Center South, Department of Pharmacology and Neurology, Nashville, Tennessee, USA

The objective of this investigation was to determine the distribution of cholinergic and noncholinergic biomarkers in discrete brain regions (cortex, stem, striatum, hippocampus, and cerebellum) of rats treated with dimethyl sulfoxide (DMSO, controls), and insecticides such as carbofuran (CARB, 1.5 mg/kg, sc), or methyl parathion (MPTH, 5 mg/kg, ip). Both insecticides produced characteristic signs of anticholinesterase nature within 5-7 min after injection. In controls, analyses of the brain regions revealed a wide variability in the values of cholinergic (acetylcholinesterase, AChE) and noncholinergic (creatine kinase, CK; and lactic dehydrogenase, LDH, and their isoenzymes) biomarkers. The highest activities of AChE and LDH were found in the striatum (166±123 µmol/g/h and 57,720±478 IU/l, respectively) and lowest in the cerebellum (118±6 µmol/g/h) and 39,480±918 IU/l, respectively). However, the activity of CK was found highest in the cerebellum (742,560±798 IU/l) and lowest in the hippocampus (353,400±11,696 IU/l). Each brain region showed a characteristic profile of CK and LDH isoenzymes. Among the CK isoenzymes, activity of CK-BB was highest (77.5-89.3%), followed by CK-MM (6.7-15.6%), and least CK-MB (0-6.9%). The cerebellum had no CK-MB activity. In all brain regions, CK-MM isoenzyme had only the CK-MM3 subform. Among the LDH isoenzymes, activity of LDH-4 was highest in all brain regions (23-40%), except the cerebellum in which LDH-1 was highest (29%). Compared to the brain, control serum contained very little CK and LDH activity, but serum had three distinct CK and five distinct LDH iso-enzymes. Unlike brain regions, serum had three CK-MM subforms. Each insecticide induced characteristic alterations in brain biomarkers. AChE activity was maximally inactivated in cortex (90.6%) with CARB, and in cerebellum (95.3%) with MPTH. With either insecticide, the least inhibition of AChE occurred in the striatum. Unlike AChE, carboxylesterase (CarbE) did not show brain regional variability in controls, and its activity was uniformly inhibited in all brain regions by CARB and comparatively greater by MPTH. CARB- or MPTH-induced characteristic alterations in CK, LDH, and their isoenzymes in the brain, which were also reflected in serum, as a result of their leakage from the brain by increased permeability due to depletion of ATP (38-57% and 33-47%, respectively) and phosphocreatine (PCr, 23-42% and 56-65%, respectively).

Key Words: biomarkers • carbofuran • methyl parathion • cytotoxicity • high-energy phosphates

Human & Experimental Toxicology, Vol. 19, No. 5, 297-308 (2000)
DOI: 10.1191/096032700678815927


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