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

R. Orie Browne^*, Liat Ben Moyal-Segal, Dominik Zumsteg, Yaron David^*, Ora Kofman, Andrea Berger, Hermona Soreq and Alon Friedman^*,1

^* Departments of Physiology and Neurosurgery, Soroka University Medical Center,

The Department of Biological Chemistry, The Life Sciences Institute, The Hebrew University of Jerusalem, Jerusalem, Israel;

Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto, Toronto, Canada; and

Department of Behavioral Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, Beersheva, Israel

¹Correspondence: Department of Physiology, Faculty for Health Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel. E-mail: alonf{at}bgu.ac.il

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.—Browne, R. O., Ben Moyal-Segal, L., Zumsteg, D., David, Y., Kofman, O., Berger, A., Soreq, H., Friedman, A. Coding region paraoxonase polymorphisms dictate accentuated neuronal reactions in chronic, sub-threshold pesticide exposure.