ABSTRACT
Organophosphate pesticides (OPs), known inhibitors of acetylcholinesterase (AChE), are used extensively throughout the world. Recent studies have focused on the ACHE/PON1 locus as a determinant of inherited susceptibility to environmental OP exposure. To explore the relationship of the corresponding gene-environment interactions with brain activity, we integrated neurophysiologic, neuropsychological, biochemical, and genetic methods. Importantly, we found that subthreshold OP exposure leads to discernible physiological consequences that are significantly influenced by inherited factors. Cortical EEG analyses by LORETA revealed significantly decreased theta activity in the hippocampus, parahippocampal regions, and the cingulate cortex, as well as increased beta activity in the prefrontal cortex of exposed individuals-areas known to play a role in cholinergic-associated cognitive functions. Through neuropsychological testing, we identified an appreciable deficit in the visual recall in exposed individuals. Other neuropsychological tests revealed no significant differences between exposed and non-exposed individuals, attesting to the specificity of our findings. Biochemical analyses of blood samples revealed increases in paraoxonase and arylesterase activities and reduced serum acetylcholinesterase activity in chronically exposed individuals. Notably, specific paraoxonase genotypes were found to be associated with these exposure-related changes in blood enzyme activities and abnormal EEG patterns. Thus, gene-environment interactions involving the ACHE/PON1 locus may be causally involved in determining the physiological response to OP exposure.
Subject(s)
Aryldialkylphosphatase/genetics , Cholinesterase Inhibitors/adverse effects , Environmental Exposure/adverse effects , Neurons/drug effects , Pesticides/adverse effects , Polymorphism, Genetic , Acetylcholinesterase/blood , Aryldialkylphosphatase/blood , Brain/pathology , Brain/physiopathology , Brain Chemistry , Carboxylic Ester Hydrolases/blood , Cognition Disorders/chemically induced , Cognition Disorders/genetics , Electroencephalography , Genetic Predisposition to Disease , Genotype , Humans , Mental Recall , Neurons/physiology , Organophosphates/adverse effectsABSTRACT
Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Due to its positively charged ammonium group, under normal conditions pyridostigmine cannot cross the blood-brain barrier (BBB) and penetrate the brain. However, several studies have suggested that under conditions in which the BBB is disrupted, pyridostigmine enters the brain, changes cortical excitability, and leads to long-lasting alterations in gene expression. The aim of this study was to characterize the mechanisms underlying pyridostigmine-induced changes in the excitability of central neurons. Using whole cell intracellular recordings in hippocampal neurons we show that pyridostigmine decreases repetitive firing adaptation and increases the appearance of excitatory postsynaptic potentials. In voltage clamp recordings, both pyridostigmine and acetylcholine (ACh) increased the frequency but not the amplitude of excitatory postsynaptic currents. These effects were reversible upon the administration of the muscarinic receptor antagonist, atropine, and were not blocked by tetrodotoxin. We conclude that pyridostigmine, by increasing free ACh levels, causes muscarinic-dependent enhancement of excitatory transmission. This mechanism may explain central side effects previously attributed to this drug as well as the potency of AChE inhibitors, including nerve-gas agents and organophosphate pesticides, in the initiation of cortical synchronization, epileptic discharge, and excitotoxic damage.
