| Exposure of Neonatal Rats to Parathion Elicits Sex-Selective Impairment of Acetylcholine Systems in Brain Regions during Adolescence and Adulthood Theodore A. Slotkin,1,2 Bethany E. Bodwell,1 Ian T. Ryde,1 Edward D. Levin,1,2 and Frederic J. Seidler 1Department of Pharmacology and Cancer Biology, and 2Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina USA Abstract
Background: Organophosphates elicit developmental neurotoxicity through multiple mechanisms other than their shared property as cholinesterase inhibitors. Accordingly, these agents may differ in their effects on specific brain circuits. Objectives: We gave parathion to neonatal rats [postnatal days (PNDs) 1–4], at daily doses of 0.1 or 0.2 mg/kg, spanning the threshold for barely detectable cholinesterase inhibition and systemic effects. Methods: We assessed neurochemical indices related to the function of acetylcholine (ACh) synapses (choline acetyltransferase, presynaptic high-affinity choline transporter, nicotinic cholinergic receptors) in brain regions comprising all the major ACh projections, with determinations carried out from adolescence to adulthood (PNDs 30, 60, and 100) . Results: Parathion exposure elicited lasting alterations in ACh markers in the frontal/parietal cortex, temporal/occipital cortex, midbrain, hippocampus, and striatum. In cerebrocortical areas, midbrain, and hippocampus, effects in males were generally greater than in females, whereas in the striatum, females were targeted preferentially. Superimposed on this general pattern, the cerebrocortical effects showed a nonmonotonic dose–response relationship, with regression of the defects at the higher parathion dose ; this relationship has been seen also after comparable treatments with chlorpyrifos and diazinon and likely represents the involvement of cholinesterase-related actions that mask or offset the effects of lower doses. Conclusions: Neonatal exposure to parathion, at doses straddling the threshold for cholinesterase inhibition, compromises indices of ACh synaptic function in adolescence and adulthood. Differences between the effects of parathion compared with chlorpyrifos or diazinon and the nonmonotonic dose–effect relationships reinforce the conclusion that various organophosphates diverge in their effects on neurodevelopment, unrelated to their anticholinesterase actions. Key words: acetylcholine, brain development, organophosphate insecticides, parathion. Environ Health Perspect 116:1308–1314 (2008) . doi:10.1289/ehp.11451 available via http://dx.doi.org/ [Online 19 May 2008]
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 This research was supported by grant ES10356 from the National Institutes of Health. T.S. and F.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 6 March 2008 ; accepted 19 May 2008.
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