Neonatal exposure to low doses of diazinon: long-term effects on neural cell development and acetylcholine systems.
BACKGROUND
The developmental neurotoxicity of organophosphate pesticides involves mechanisms other than their shared property of cholinesterase inhibition.


OBJECTIVE
We gave diazinon (DZN) to newborn rats on postnatal days 1-4, using doses (0.5 or 2 mg/kg) spanning the threshold for barely detectable cholinesterase inhibition.


METHODS
We then evaluated the lasting effects on indices of neural cell number and size, and on functional markers of acetylcholine (ACh) synapses (choline acetyltransferase, presynaptic high-affinity choline transporter, nicotinic cholinergic receptors) in a variety of brain regions.


RESULTS
DZN exposure produced a significant overall increase in cell-packing density in adolescence and adulthood, suggestive of neuronal loss and reactive gliosis; however, some regions (temporal/occipital cortex, striatum) showed evidence of net cell loss, reflecting a greater sensitivity to neurotoxic effects of DZN. Deficits were seen in ACh markers in cerebrocortical areas and the hippocampus, regions enriched in ACh projections. In contrast, there were no significant effects in the midbrain, the major locus for ACh cell bodies. The striatum showed a unique pattern, with robust initial elevations in the ACh markers that regressed in adulthood to normal or subnormal values.


CONCLUSIONS
These results indicate that developmental exposures to apparently nontoxic doses of DZN compromise neural cell development and alter ACh synaptic function in adolescence and adulthood. The patterns seen here differ substantially from those seen in earlier work with chlorpyrifos, reinforcing the concept that the various organophosphates have fundamentally different effects on the developmental trajectories of specific neurotransmitter systems, unrelated to their shared action as cholinesterase inhibitors.
Slotkin
Theodore A
TA
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. t.slotkin@duke.edu
Bodwell
Bethany E
BE
Levin
Edward D
ED
Seidler
Frederic J
FJ
D000109:Acetylcholine / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003976:Diazinon / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D000109:Acetylcholine; D003976:Diazinon