Coding region paraoxonase polymorphisms dictate accentuated neuronal reactions in chronic, sub‐threshold pesticide exposure

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.

Paraoxonase 1 and Its Relationship With Pesticide Biomarkers in Indigenous Mexican Farmworkers

“…activity toward diazoxon in both cases and in controls. Also, Browne et al 70 studied workers with exposure to OP and found a significant decrease of AChE and a compensatory increase in paraoxonase as a result of such exposure. According to the authors, the serum levels of these enzymes are the result of a complex interaction between genetic (genotype) and environmental (exposure to chemicals) factors and the locus determining AChE/PON1 represents an innate susceptibility to OP.…”

Chronic administration of isocarbophos induces vascular cognitive impairment in rats

“…Evidence from epidemiology indicate that chronic organophosphorus exposure would lead to the impairments of neurocognitive functions 12, 13, 14, 15. Thus, we suggested that chronic organophosphorus exposure might induce cerebrovascular dysfunctions and sequential cognitive impairments.…”

Transgenic inactivation of acetylcholinesterase impairs homeostasis in mouse hippocampal granule cells

“…Carriers constitutively overexpress AChE (Shapira et al, 2000), but are unable to further increase AChE expression and specifically induce the AChE-R variant to counteract ACh hyperexcitability; this could result in disturbed neurogenesis, in turn predisposing to posttraumatic stress disorder which is thought to result at least in part from defective neurogenesis (Vermetten et al, 2003). Correspondingly, carriers of the above polymorphisms demonstrate state anxiety and acute electroencephalographic reactions to insecticide exposure (Browne et al, 2006).…”