Exposure of Neonatal Rats to Parathion Elicits Sex-Selective Impairment of Acetylcholine Systems in Brain Regions during Adolescence and Adulthood

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Abstract
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. 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. 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). 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. 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 non-monotonic dose–effect relationships reinforce the conclusion that various organophosphates diverge in their effects on neurodevelopment, unrelated to their anticholinesterase actions.

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