Neurochemical effects of chronic dietary and repeated high-level acute exposure to chlorpyrifos in rats.
Very little is known about the effects of chronic exposure to relatively low levels of anticholinesterase insecticides or how the effects of chronic exposure compare to those of higher, intermittent exposure. To that end, adult male rats were fed an anticholinesterase insecticide, chlorpyrifos (CPF), for 1 year at three levels of dietary exposure: 0, 1, or 5 mg/kg/day (0+oil, 1+oil, and 5+oil). In addition, half of each of these groups also received a bolus dosage of CPF in corn oil ("spiked" animals; 60 mg/kg initially and 45 mg/kg thereafter) every 2 months (0+CPF, 1+CPF, 5+CPF). Animals were analyzed after 6 or 12 months of dosing, and again 3 months after cessation of dosing (i.e., "recovery" animals-six experimental groups with n = 4-6/group/time point). Cholinesterase (ChE) activity was measured in retina, whole blood, plasma, red blood cells, diaphragm, and brain [pons, striatum, and the rest of the brain (referred to simply as "brain")]. Muscarinic receptor density was assessed in retina, pons, and brain, whereas dopamine transporter density and the levels of dopamine and its metabolites were assessed in striatum. Cholinesterase activity at 6 and 12 months was not different in any of the tissues, indicating that a steady state had been reached prior to 6 months. The 1+oil group animals showed ChE inhibition only in the blood, whereas the 5+oil group exhibited > or = 50% ChE inhibition in all tissues tested. One day after the bolus dose, all three groups (0+CPF, 1+CPF, 5+CPF) showed > or = 70% ChE inhibition in all tissues. Muscarinic receptor density decreased only in the brain of the 5+oil and 5+CPF groups, whereas dopamine transporter density increased only at 6 months in all three spiked groups. Striatal dopamine or dopamine metabolite levels did not change at any time. Three months after CPF dosing ended, all end points had returned to control levels. These data indicate that, although chronic feeding with or without intermittent spiked dosages with CPF produces substantial biochemical changes in a dose- and tissue-related manner, there are no persistent biochemical changes.
Padilla
Stephanie
S
Neurotoxicology Division, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. Padilla.Stephanie@epa.gov
Marshall
Renée S
RS
Hunter
Deborah L
DL
Oxendine
Sharon
S
Moser
Virginia C
VC
Southerland
Stanley B
SB
Mailman
Richard B
RB
D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism*; D002908:Chronic Disease; D004032:Diet; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008454:Mazindol / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D011976:Receptors, Muscarinic / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007306:Insecticides; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011976:Receptors, Muscarinic; D008454:Mazindol; D002802:Cholinesterases; D004390:Chlorpyrifos; D004298:Dopamine