Association of Paraoxonase (PON1) Polymorphism with Risk of Neurotoxicity in Agricultural Workers

Abstract

P-283 Introduction: In recent years, the use of pesticides has reached massive proportions worldwide; within these compounds are the organophosphates (OP). The adverse effects caused by these pesticides are related to their ability to inhibit the acetylcholinesterase (AChE) activity, which can result in muscarinic and nicotinic symptoms as well as muscle weakness. The human paraoxonase (PON1) enzyme has a role in detoxifying OP by hydrolyzing the active oxons and some polymorphisms in PON1 gene, particularly at position 192, are known to modify the catalytic activity of the enzyme and have been associated with the susceptibility to OP neurotoxicity. Therefore, the aim of this study was to evaluate PON1 phenotype and genotype (polymorphisms at positions -108 and 192) and determine whether they are related to AChE inhibition in agricultural workers exposed to OP. Methods: A cross sectional study was carried out in 84 male unrelated agricultural workers (mean age 42 years) with history of occupational exposure to pesticides. Participants were divided in: sprayers (43%) and non-sprayers (57%). Information about pesticides use, diet, demographic characteristics and lifestyle were collected by direct interviews. Signed informed consent was obtained before collecting blood samples. Acetylcholinesterase activity was determined by the Ellman′s method, PON1 activity was assayed using phenylacetate and paraoxon as substrates and PON1 genotype at positions -108 and 192 were determined by PCR-RFLP. The study was approved by the Institutional Review Board. Results: A wide interindividual variability in PON1 activity was found with a unimodal distribution; the range of enzymatic activity towards phenylacetate was 60 to 381U/mL, and 59 to 1559U/L towards paraoxon. The allele frequencies were: 0.45 for C and 0.55 for T at position -108 and 0.48 for R and 0.52 for Q at position 192. Both polymorphisms were associated with PON1 activities. Agricultural workers had lower AChE activity (4.9U/mL; p<0.05) than a control population (5.5U/mL) previously studied. Multivariate analysis revealed a significant lower AChE activity among the sprayers (4.5U/mL) compared to non-sprayers (5.3U/mL). Finally, individuals with PON1 192QQ genotype showed 94% of possibility of having lower AChE activity than the mean observed in a control population (5.3U/mL). The QQ allele has been associated with lower activity towards paraoxon and clorpirifos oxon, metabolites of two OP compounds most used in agriculture. Conclusion: These results suggest that PON1 192 polymorphism can be use as a susceptibility factor to OP neurotoxicity, considering AChE activity as the biomarker in occupationally exposed populations.