| Neonatal Exposure to Low Doses of Diazinon: Long-Term Effects on Neural Cell Development and Acetylcholine Systems Theodore A. Slotkin,1,2 Bethany E. Bodwell,1 Edward D. Levin,1,2 and Frederic J. Seidler1 1Department of Pharmacology & Cancer Biology, and 2Department of Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, North Carolina USA Abstract
Background: The developmental neurotoxicity of organophosphate pesticides involves mechanisms other than their shared property of cholinesterase inhibition. Objectives: 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. Key words: acetylcholine, brain development, diazinon, organophosphate insecticides. Environ Health Perspect 116:340–348 (2008) . doi:10.1289/ehp.11005 available via http://dx.doi.org/ [Online 13 December 2007]
Address correspondence to T.A. Slotkin, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710 USA. Telephone: (919) 681-8015. Fax: (919) 684-8197. E-mail: t.slotkin@duke.edu We thank K. Faust and J. Johnson for technical assistance. This research was supported by grant ES10356 from the National Institutes of Health. T.A.S. and F.J.S. have provided expert witness testimony on behalf of government agencies, corporations, and/or individuals. The authors declare they have no competing financial interests. Received 22 October 2007 ; accepted 13 December 2007.
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